Wei Ding

All Publications

• Incidence of Richter transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma in the targeted therapy era. Leukemia Hampel, P. J., Rabe, K. G., Wang, Y., Hwang, S. R., Kenderian, S. S., Muchtar, E., Leis, J. F., Koehler, A. B., Tsang, M., Hilal, T., Parrondo, R., Bailen, R. J., Schwager, S. M., Hanson, C. A., Braggio, E., Slager, S. L., Shi, M., Zepeda-Mendoza, C. J., Van Dyke, D. L., Shanafelt, T. D., King, R. L., Call, T. G., Kay, N. E., Ding, W., Parikh, S. A. 2024

  View details for DOI 10.1038/s41375-024-02492-4

  View details for PubMedID 39658628

  View details for PubMedCentralID 3954047

• Efficacy of pembrolizumab monotherapy and in combination with BCR inhibitors for Richter transformation of chronic lymphocytic leukemia (CLL) Wang, Y., LaPlant, B. R., Parikh, S., Leis, J., Call, T. G., Shanafelt, T. D., He, R., Micallef, I. N., Nowakowski, G. S., Habermann, T., Witzig, T. E., Koehler, A. B., Hampel, P., Kenderian, S., Muchtar, E., Aitken, C. N., Sinha, S., Kay, N. E., Ansell, S. M., Ding, W. LIPPINCOTT WILLIAMS & WILKINS. 2024

  View details for Web of Science ID 001275557401698

• Tumor mutational load is prognostic for progression to therapy among high-count monoclonal B-cell lymphocytosis (HCMBL). Blood advances Kleinstern, G., Boddicker, N. J., O'Brien, D. R., Allmer, C., Rabe, K. G., Norman, A. D., Griffin, R., Yan, H., Ma, T., Call, T. G., Bruins, L., Brown, S., Bonolo de Campos, C., Hanson, C. A., Leis, J. F., Ding, W., Vachon, C. M., Kay, N. E., Oakes, C. C., Parker, A., Brander, D. M., Weinberg, J. B., Furman, R. R., Shanafelt, T. D., Cerhan, J. R., Parikh, S. A., Braggio, E., Slager, S. L. 2024

  Abstract

  HCMBL is a precursor condition to chronic lymphocytic leukemia (CLL). We have shown that among individuals with HCMBL the CLL-International Prognostic Index (CLL-IPI) is prognostic for time-to-first therapy (TTFT). Little is known about the prognostic impact of somatically mutated genes among individuals with HCMBL. We sequenced DNA from 371 HCMBL individuals using a targeted sequencing panel of 59 recurrently mutated genes in CLL to identify high-impact mutations. We compared the sequencing results to that of our treatment-naïve CLL cohort(N=855) and employed Cox regression to estimate hazard ratios and 95% confidence intervals (CI) for associations with TTFT. Compared to CLL, the frequencies of any mutated genes were lower in HCMBL (70% versus 52%). At 10-years, 37% of HCMBL individuals with any mutated gene had progressed requiring treatment compared to 10% among HCMBL individuals with no mutations; this led to 5.4-fold shorter TTFT (95%CI:2.6-11.0) among HCMBL with any mutated gene versus none, independent of CLL-IPI. When considering individuals with low-risk of progression according to CLL-IPI, HCMBL individuals with any mutations had 4.3-fold shorter TTFT (95%CI:1.6-11.8) versus those with none. Finally, when considering both CLL-IPI and any mutated gene status, we observed HCMBL individuals who were high-risk for both prognostic factors with worse prognosis compared to low-risk CLL patients (i.e., 5-year progression rate of 32% versus 21%, respectively). Among HCMBL, the frequency of somatically mutated genes at diagnosis is lower than that of CLL. Accounting for both the number of mutated genes and CLL-IPI can identify HCMBL individuals with more aggressive clinical course.

  View details for DOI 10.1182/bloodadvances.2023012242

  View details for PubMedID 38359367

• Prediction of outcomes for high-count monoclonal B lymphocytosis using an epigenetic and immunogenetic signature. Blood Abdelbaky, S., Giacopelli, B., Rabe, K. G., Yamaguchi, K., Wu, Y. Z., Yan, H., Shanafelt, T. D., Parikh, S. A., Ding, W., Hampel, P. J., Brown, S., Cerhan, J. R., Vachon, C. M., Kay, N. E., Hanson, C. A., Parker, A., Braggio, E., Slager, S. L., Oakes, C. C. 2024

  Abstract

  Monoclonal B cell lymphocytosis (MBL) progresses to chronic lymphocytic leukemia (CLL) requiring therapy at 1-5%/year. Improved prediction of progression would greatly benefit individuals with MBL. CLL patients separate into three distinct epigenetic subtypes (epitypes) with high prognostic significance, and recently the intermediate epitype has been shown to be enriched for high-risk IGLV3-21 rearrangements, impacting outcomes for these patients. Here we employed this combined strategy to generate the epigenetic and light chain immunoglobulin (ELCLV3-21) signature to classify 219 individuals with MBL. The ELCLV3-21 high-risk signature distinguished MBL individuals with a high probability of progression (39.9% and 71.1% at 5 and 10 years, respectively). ELCLV3-21 improved the accuracy of predicting time to therapy for MBL individuals compared to other established prognostic indicators, including the CLL international prognostic index (c-statistic 0.767 versus 0.668, respectively). Comparing ELCLV3-21 risk groups in MBL versus a cohort of 226 CLL patients revealed ELCLV3-21 high-risk MBL individuals had significantly shorter time to therapy (P=0.003) and reduced OS (P=0.03) compared to ELCLV3-21 low-risk CLL. These results highlight the power of the ELCLV3-21 approach to identify individuals with a higher likelihood of adverse clinical outcome and may provide a more accurate approach to classify individuals with small B-cell clones.

  View details for DOI 10.1182/blood.2023022180

  View details for PubMedID 38194687

• PD-1 Expression in Lymphoma Cells Mediates Cellular Proliferation By Engaging Phosphatase SHP-1/SHP-2 Sinha, S., Price-Troska, T., Tian, S., Sakemura, R., Yan, H., Boysen, J., Wang, Z., Wu, X., He, R., Shi, M., Wang, Y., Klee, E. W., Parikh, S. A., Hampel, P. J., Call, T. G., Leis, J. F., Shanafelt, T. D., Ansell, S. M., Kenderian, S. S., Kay, N. E., Ding, W. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-177755

  View details for Web of Science ID 001159740303124

• Results of a phase 3 study of IVO vs IO for previously untreated older patients (pts) with chronic lymphocytic leukemia (CLL) and impact of COVID-19 (Alliance). Woyach, J., Yin, J., Brown, J. R., Dinner, S., Lozanski, G., Little, R. F., Miller, C., Damarla, V., Coutre, S. E., Ding, W., Hill, B. T., Burbano, G., Ruppert, A. S., Wall, A. K. M., Feldman, D., Dib, E. G., Erba, H., Litzow, M., Stone, R. M., Byrd, J. C. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for Web of Science ID 001053772003445

• Results of a phase 3 study of IVO vs IO for previously untreated older patients (pts) with chronic lymphocytic leukemia (CLL) and impact of COVID-19 (Alliance). Woyach, J., Yin, J., Brown, J. R., Dinner, S., Lozanski, G., Little, R. F., Miller, C., Damarla, V., Coutre, S. E., Ding, W., Hill, B. T., Perez Burbano, G., Ruppert, A. S., Wall, A. K. M., Feldman, D., Dib, E. G., Erba, H., Litzow, M., Stone, R. M., Byrd, J. C. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for DOI 10.1200/JCO.2023.41.16_suppl.7500

  View details for Web of Science ID 001555447800041

• Long-Term Results of Alliance A041202 Show Continued Advantage of Ibrutinib-Based Regimens Compared with Bendamustine Plus Rituximab (BR) Chemoimmunotherapy Woyach, J. A., Ruppert, A. S., Heerema, N. A., Zhao, W., Booth, A. M., Ding, W., Bartlett, N. L., Brander, D. M., Barr, P. M., Rogers, K., Parikh, S. A., Coutre, S., Lozanski, G., Nattam, S., Larson, R. A., Erba, H. P., Litzow, M. R., Blachly, J. S., Owen, C., Kuzma, C., Abramson, J. S., Brown, J. R., Little, R. F., Smith, S. E., Stone, R. M., Mandrekar, S. J., Byrd, J. C. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-153146

  View details for Web of Science ID 000736398802179

• Clinical Characteristics and Outcomes of Patients with Chronic Lymphocytic Leukemia (CLL), 80 Years of Age or Older Hampel, P., Call, T., Rabe, K., Achenbach, S., Muchtar, E., Kenderian, S., Wang, Y., Koehler, A., Leis, J., Schwager, S., Van Dyke, D., Shi, M., Hanson, C., Shanafelt, T., Braggio, E., Slager, S., Kay, N., Ding, W., Parikh, S. CIG MEDIA GROUP, LP. 2021: S324-S325

  View details for Web of Science ID 000691910500200

• Cause of death in patients with newly diagnosed chronic lymphocytic leukemia (CLL) stratified by the CLL-International Prognostic Index. Blood cancer journal Wang, Y., Achenbach, S. J., Rabe, K. G., Shanafelt, T. D., Call, T. G., Ding, W., Kenderian, S. S., Muchtar, E., Leis, J. F., Koehler, A. B., Schwager, S. M., Cerhan, J. R., Slager, S. L., Kay, N. E., Parikh, S. A. 2021; 11 (8): 140

  View details for DOI 10.1038/s41408-021-00532-1

  View details for PubMedID 34354039

• Adverse event burden in older patients with CLL receiving bendamustine plus rituximab or ibrutinib regimens: Alliance A041202. Leukemia Ruppert, A. S., Booth, A. M., Ding, W., Bartlett, N. L., Brander, D. M., Coutre, S., Brown, J. R., Nattam, S., Larson, R. A., Erba, H., Litzow, M., Owen, C., Kuzma, C. S., Abramson, J. S., Little, R. F., Smith, S. E., Stone, R. M., Byrd, J. C., Mandrekar, S. J., Woyach, J. A. 2021

  Abstract

  Ibrutinib has superior progression-free survival compared with bendamustine plus rituximab (BR) in older CLL patients, however, differences in treatment duration, six monthly BR cycles versus continuous ibrutinib, complicate adverse event (AE) comparisons. We introduce the AE burden score (AEsc) to compare AEs, calculated for each patient by summing over products of reporting period length and grade for each all-cause grade 1-4 AE and dividing by the length of time over which AEs are assessed. A total of 176 patients received BR and 361 ibrutinib alone or with six cycles of rituximab. At 38 months median follow-up, 64% remained on ibrutinib. Median AEsc was higher with BR versus ibrutinib in the first six cycles (7.2 versus 4.9, p<0.0001). Within ibrutinib arms, median AEsc decreased significantly to 3.7 after six cycles (p<0.0001). 10% and 14% of BR and ibrutinib patients discontinued treatment for AEs. In ibrutinib arms, cumulative incidence of grade 3 or higher atrial fibrillation, hypertension, and infection (AEs of clinical interest) at 12 months was 4.5%, 17.5%, and 12.8%, respectively, and increased more slowly thereafter to 7.7%, 25.4%, and 20.5% at 36 months. Analytical tools including the AEsc and cumulative incidence of AEs can help to better characterize AE burden over time. ClinicalTrials.gov identifier: NCT01886872.

  View details for DOI 10.1038/s41375-021-01342-x

  View details for PubMedID 34274940

• The CLL-international prognostic index (CLL-IPI) predicts outcomes in monoclonal B-cell lymphocytosis and Rai 0 CLL. Blood Parikh, S. A., Rabe, K. G., Kay, N. E., Call, T. G., Ding, W., Leis, J. F., Kenderian, S. S., Muchtar, E., Wang, Y., Koehler, A., Schwager, S. M., Lesnick, C., Kleinstern, G., Van Dyke, D. L., Hanson, C. A., Braggio, E., Slager, S. L., Shanafelt, T. D. 2021

  Abstract

  The utility of the chronic lymphocytic leukemia - international prognostic index (CLL-IPI) in predicting outcomes of individuals with Rai 0 stage CLL and monoclonal B-cell lymphocytosis (MBL) is unclear. We identified 969 individuals (415 MBL and 554 Rai 0 CLL; median age=64 years, 65% men) seen at Mayo Clinic between 1/1/2001 and 10/1/2018, and ascertained time to first therapy (TTFT) and overall survival (OS). After a median follow up of 7 years, the risk of disease progression needing therapy was 2.9%/year for MBL (median=not reached) and 5%/year for Rai 0 CLL (median=10.4 years). Among patients with low, intermediate and high/very high risk CLL-IPI risk groups, the estimated 5-year risk of TTFT was 13.5%, 30%, and 58%, respectively, p<0.0001 (c-statistic=0.69); and the estimated 5-year OS was 96.3%, 91.5%, and 76%, respectively, p<0.0001 (c-statistic:0.65). In a multivariable analysis of absolute B-cell count with individual factors of the CLL-IPI, the absolute B-cell count was associated with shorter TTFT (hazard ratio [HR] for each 10 x 109/L increase: 1.31; p<0.0001), and shorter OS (HR: 1.1; p=0.02). The OS of the entire cohort was similar to age- and sex-matched general population of Minnesota (p=0.17), although Rai 0 CLL patients with high and very high risk CLL-IPI score had significantly shorter OS (p=0.01, and p=0.0001, respectively). The results of this study demonstrate the ability of CLL-IPI to predict time from diagnosis to first treatment (an endpoint not impacted by therapy) in a large cohort of patients whose only manifestation of disease is a circulating clonal lymphocyte population.

  View details for DOI 10.1182/blood.2020009813

  View details for PubMedID 33876228

• The humoral immune response to high-dose influenza vaccine in persons with monoclonal B-cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL). Vaccine Whitaker, J. A., Parikh, S. A., Shanafelt, T. D., Kay, N. E., Kennedy, R. B., Grill, D. E., Goergen, K. M., Call, T. G., Kendarian, S. S., Ding, W., Poland, G. A. 2021

  Abstract

  BACKGROUND: Limited data are available regarding the immunogenicity of high-dose influenza vaccine among persons with chronic lymphocytic leukemia (CLL) and monoclonal B cell lymphocytosis (MBL).METHODS: A prospective pilot study of humoral immune responses to 2013-2014 and 2014-2015 high-dose trivalent influenza vaccine (HD IIV; Fluzone High-Dose; Sanofi Pasteur) was conducted among individuals with MBL and previously untreated CLL. Serum hemagglutination inhibition (HAI) antibody titers were measured at baseline and Day 28 after vaccination; seroprotection and seroconversion rates were determined. Memory B cell responses were assessed by B-cell enzyme-linked immune absorbent spotassays.RESULTS: Thirty subjects (17 CLL and 13 MBL) were included. Median age was 69.5years. Day 28 seroprotection rates for the cohort were 19/30 (63.3%) for A/H1N1; 21/23 (91.3%) for A/H3N2; and 13/30 (43.3%) for influenza B. Those with MBL achieved higher day 28 HAI geometric mean titers (54.1 [4.9, 600.1] vs. 12.1 [1.3, 110.1]; p=0.01) and higher Day 28 seroprotection rates (76.9% vs. 17.6%; p=0.002) against the influenza B-vaccine strain virus than those with CLL.CONCLUSIONS: Immunogenicity of the HD IIV3 in patients with CLL and MBL is lower than reported in healthy adults. Immunogenicity to influenza B was greater in those with MBL than CLL.

  View details for DOI 10.1016/j.vaccine.2021.01.001

  View details for PubMedID 33461835

• Delineation of clinical and biological factors associated with cutaneous squamous cell carcinoma amongst chronic lymphocytic leukemia patients. Journal of the American Academy of Dermatology Kleinstern, G., Rishi, A., Achenbach, S. J., Rabe, K. G., Kay, N. E., Shanafelt, T. D., Ding, W., Leis, J. F., Norman, A. D., Call, T. G., Cerhan, J. R., Parikh, S. A., Baum, C. L., Slager, S. L. 2020

  Abstract

  BACKGROUND: The incidence of cutaneous squamous cell carcinoma (SCC) in chronic lymphocytic leukemia (CLL) patients is significantly higher compared to age- and sex- matched controls.OBJECTIVE: To evaluate the association of factors associated with SCC risk.METHODS: Clinical CLL and SCC data were obtained from Mayo Clinic CLL resource and self-reported questionnaires among newly diagnosed CLL patients. We computed the CLL International Prognostic Index (CLL-IPI), from CLL prognostic factors, and a polygenetic risk score (PRS) from SCC susceptibility variants. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).RESULTS: Among 1269 CLL patients, the median follow-up was 7 years, and 124 patients subsequently developed SCC. Significant associations with SCC risk were history of skin cancer (HR=4.80,CI:3.37-6.83), CLL-IPI (HR=1.42,CI:1.13-1.80), and PRS (HR=2.58,CI:1.50-4.43). In a multivariable model, these factors were independent predictors (c-statistic=0.69,CI:0.62-0.76). T-cell immunosuppressive treatments was also associated with SCC risk (HR=2.29,CI:1.47-3.55, adjusted for age, sex, and prior SCC).LIMITATIONS: Sample size decreases when combining all risk factors in a single model.CONCLUSION: SCC risk includes history of skin cancer, an aggressive disease at time of CLL diagnosis, receiving T-cell immunosuppressive treatments, and high-PRS. Future studies should develop prediction models that include these factors to improved screening guidelines.

  View details for DOI 10.1016/j.jaad.2020.06.1024

  View details for PubMedID 32682027

• Atrial fibrillation in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib: risk prediction, management, and clinical outcomes. Annals of hematology Archibald, W. J., Rabe, K. G., Kabat, B. F., Herrmann, J., Ding, W., Kay, N. E., Kenderian, S. S., Muchtar, E., Leis, J. F., Wang, Y., Chanan-Khan, A. A., Schwager, S. M., Koehler, A. B., Fonder, A. L., Slager, S. L., Shanafelt, T. D., Call, T. G., Parikh, S. A. 2020

  Abstract

  BACKGROUND: Ibrutinib therapy is associated with an increased risk of atrial fibrillation (AF) in chronic lymphocytic leukemia (CLL). Risk assessment tools and outcomes of AF in these patients are not well described.METHODS: We performed a retrospective review of patients with CLL treated with ibrutinib at Mayo Clinic between October 2012 and November 2018.RESULTS: Two hundred ninety-eight patients were identified with a median time on ibrutinib of 19 months (range 0.23-69.7 months). Fifty-one patients developed treatment-emergent AF; the risk of treatment-emergent AF at 6 months, 1 year, and 2 years was 9%, 12%, and 16%, respectively. The following were associated with an increased risk of treatment-emergent AF on multivariable analyses: past history of AF (hazard ratio [HR] 3.5, p = 0.0072) and heart failure (HR 3.4, p = 0.0028). Most patients are able to continue ibrutinib therapy (dose reduced in 43%). Development of treatment-emergent AF was associated with shorter event-free survival (EFS; HR 2.0, p = 0.02) and shorter overall survival (OS; HR 3.2, p = 0.001), after adjusting for age, prior treatment status, TP53 disruption, heart failure, valvular disease, and past history of AF.CONCLUSIONS: Patient comorbidities, rather than CLL-related factors, predict risk of treatment-emergent AF in patients treated with ibrutinib. Although the vast majority of patients with treatment-emergent AF are able to continue ibrutinib (with dose reduction in 43%), treatment-emergent AF appears to be associated with worse outcomes, independent of other adverse prognostic factors.

  View details for DOI 10.1007/s00277-020-04094-3

  View details for PubMedID 32488603

• Cause of death in patients with newly diagnosed chronic lymphocytic leukemia (CLL) stratified by the CLL-International Prognostic Index (CLL-IPI). Wang, Y., Achenbach, S. J., Rabe, K. G., Shanafelt, T. D., Call, T., Ding, W., Kenderian, S., Muchtar, E., Leis, J., Koehler, A., Schwager, S. M., Cerhan, J., Slager, S. L., Kay, N. E., Parikh, S. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000560368303246

• Toxicity burden in older patients with chronic lymphocytic leukemia (CLL) receiving bendamustine with rituximab (BR) or ibrutinib (IB) regimens: Alliance A041202. Ruppert, A. S., Mandrekar, S. J., Booth, A. M., Ding, W., Bartlett, N. L., Brander, D. M., Coutre, S. E., Brown, J. R., Nattam, S. R., Larson, R. A., Erba, H., Litzow, M., Owen, C., Kuzma, C. S., Abramson, J. S., Little, R. F., Smith, S. E., Stone, R. M., Byrd, J. C., Woyach, J. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000560368307370

• The impact of dose modification and temporary interruption of ibrutinib on outcomes of chronic lymphocytic leukemia patients in routine clinical practice. Cancer medicine Parikh, S. A., Achenbach, S. J., Call, T. G., Rabe, K. G., Ding, W., Leis, J. F., Kenderian, S. S., Chanan-Khan, A. A., Koehler, A. B., Schwager, S. M., Muchtar, E., Fonder, A. L., McCullough, K. B., Nedved, A. N., Smith, M. D., Slager, S. L., Kay, N. E., Finnes, H. D., Shanafelt, T. D. 2020

  Abstract

  To study the impact of dose modification and temporary interruption of ibrutinib in routine clinical practice, we conducted a retrospective study of consecutive CLL patients treated with ibrutinib outside the context of a clinical trial at Mayo Clinic, (Rochester, MN) from 11/2013 to 12/2017. Of 209 patients, 131 (74%) had unmutated IGHV, 38 (20%) had TP53 disruption, and 47 (22%) were previously untreated. A total of 87/209 (42%) patients started reduced dose ibrutinib (<420mg daily; n=43, physician preference; n=33, concomitant medications; and n=11, other). During 281 person-years of treatment, 91/209 patients had temporary dose interruption (54%, nonhematologic toxicity; 29%, surgical procedures; 10%, hematologic toxicity; and 7%, other). After a median follow-up of 24months, the estimated median event-free survival (EFS) was 36months, and median overall survival (OS) was not reached. On multivariable analyses, temporary ibrutinib interruption (hazard ratio [HR]: 2.37, P=.006) and TP53 disruption at ibrutinib initiation (HR: 1.81, P=.048) were associated with shorter EFS, whereas only TP53 disruption (HR: 2.38, P=.015) was associated with shorter OS. Initial ibrutinib dose and dose modification during therapy did not appear to impact EFS or OS. These findings illustrate the challenges associated with continuous oral therapy with ibrutinib in patients with CLL.

  View details for DOI 10.1002/cam4.2998

  View details for PubMedID 32187452

• The etiology of pleural effusions requiring thoracentesis in patients with chronic lymphocytic leukemia (CLL) Koehler, A., Ayed, A., Albitar, H., Call, T., Rabe, K., Ding, W., Kenderian, S., Leis, J., Muchtar, E., Hayman, S., Fonder, A., Schwager, S., Slager, S., Pinto, C., Kay, N., Shanafelt, T., Iyer, V., Parikh, S. TAYLOR & FRANCIS LTD. 2020: 229–31

  View details for Web of Science ID 000534385400161

• Tumor mutational load predicts time to first treatment in chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis beyond the CLL international prognostic index. American journal of hematology Kleinstern, G. n., O'Brien, D. R., Li, X. n., Tian, S. n., Kabat, B. F., Rabe, K. G., Norman, A. D., Yan, H. n., Vachon, C. M., Boddicker, N. J., Call, T. G., Parikh, S. A., Bruins, L. n., de Campos, C. B., Leis, J. F., Shanafelt, T. D., Ding, W. n., Cerhan, J. R., Kay, N. E., Slager, S. L., Braggio, E. n. 2020

  Abstract

  Next-generation sequencing identified ~60 genes recurrently mutated in chronic lymphocytic leukemia (CLL). We examined the additive prognostic value of the total number of recurrently mutated CLL genes [i.e., tumor mutational load (TML)] or the individually mutated genes beyond the CLL international prognostic index (CLL-IPI) in newly diagnosed CLL and high-count monoclonal B-cell lymphocytosis (HC MBL). We sequenced 59 genes among 557 individuals (112 HC MBL/445 CLL) in a multi-stage design, to estimate hazard ratios (HR) and 95% confidence intervals (CI) for time-to-first treatment (TTT), adjusted for CLL-IPI and sex. TML was associated with shorter TTT in the discovery and validation cohorts, with a combined estimate of continuous HR=1.27 (CI:1.17-1.39, P=2.6x10-8 ; c-statistic=0.76). When stratified by CLL-IPI, the association of TML with TTT was stronger and validated within low/intermediate risk (combined HR=1.54, CI:1.37-1.72, P=7.0x10-14 ). Overall, 80% of low/intermediate CLL-IPI cases with 2+ mutated genes progressed to require therapy within 5 years, compared to 24% among those without mutations. TML was also associated with shorter TTT in the HC MBL cohort (HR=1.53, CI:1.12-2.07, P=0.007; c-statistic=0.71). TML is a strong prognostic factor for TTT independent of CLL-IPI, especially among low/intermediate CLL-IPI risk and a better predictor than any single gene. Mutational screening at early stages may improve risk stratification and better predict TTT. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ajh.25831

  View details for PubMedID 32279347

• Atrial fibrillation (AF) in patients with CLL treated with ibrutinib: Assessing prediction models and clinical outcomes. Archibald, W., Rabe, K. G., Kabat, B., Call, T., Ding, W., Kay, N. E., Kenderian, S., Muchtar, E., Leis, J., Schwager, S. M., Koehler, A., Fonder, A. L., Slager, S. L., Shanafelt, T. D., Parikh, S. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for Web of Science ID 000487345806284

• Rapid disease progression following discontinuation of ibrutinib in patients with chronic lymphocytic leukemia treated in routine clinical practice LEUKEMIA & LYMPHOMA Hampel, P. J., Ding, W., Call, T. G., Rabe, K. G., Kenderian, S. S., Witzig, T. E., Muchtar, E., Leis, J. F., Chanan-Khan, A. A., Koehler, A. B., Fonder, A. L., Schwager, S. M., Slager, S. L., Shanafelt, T. D., Kay, N. E., Parikh, S. A. 2019

  View details for DOI 10.1080/10428194.2019.1602268

  View details for Web of Science ID 000469572200001

• Rapid disease progression following discontinuation of ibrutinib in patients with chronic lymphocytic leukemia treated in routine clinical practice. Leukemia & lymphoma Hampel, P. J., Ding, W. n., Call, T. G., Rabe, K. G., Kenderian, S. S., Witzig, T. E., Muchtar, E. n., Leis, J. F., Chanan-Khan, A. A., Koehler, A. B., Fonder, A. L., Schwager, S. M., Slager, S. L., Shanafelt, T. D., Kay, N. E., Parikh, S. A. 2019: 1–8

  Abstract

  We identified all patients with chronic lymphocytic leukemia at Mayo Clinic treated with ibrutinib outside the context of a clinical trial; timing and reasons for discontinuation were ascertained, as were symptoms, exam and radiographic findings, and laboratory changes following discontinuation. Of 202 patients who received ibrutinib, 52 discontinued therapy (estimated 1- and 2-year risk of discontinuation 18% and 28%, respectively). The most common reasons for discontinuation were toxicity (56%) and progression of disease (32%, including Richter's transformation in 15%). Rapid progression of disease within 4 weeks after discontinuation was observed in 9/36 (25%) patients with adequate records for review, mostly in those stopping ibrutinib for disease progression (n = 8) rather than toxicity (n = 1). This was evident by sudden worsening of disease-related symptoms (n = 9), exam/radiographic changes (n = 7), and laboratory changes (n = 8). An estimated one in every three patients discontinued ibrutinib by 2 years, with 25% developing rapid disease progression afterwards.

  View details for PubMedID 31014142

• Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL NEW ENGLAND JOURNAL OF MEDICINE Woyach, J. A., Ruppert, A. S., Heerema, N. A., Zhao, W., Booth, A. M., Ding, W., Bartlett, N. L., Brander, D. M., Barr, P. M., Rogers, K. A., Parikh, S. A., Coutre, S., Hurria, A., Brown, J. R., Lozanski, G., Blachly, J. S., Ozer, H. G., Major-Elechi, B., Fruth, B., Nattam, S., Larson, R. A., Erba, H., Litzow, M., Owen, C., Kuzma, C., Abramson, J. S., Little, R. F., Smith, S. E., Stone, R. M., Mandrekar, S. J., Byrd, J. C. 2018; 379 (26): 2517-2528

  View details for DOI 10.1056/NEJMoa1812836

  View details for Web of Science ID 000454351100007

• IGH translocations in chronic lymphocytic leukemia (CLL): clinicopathologic features and clinical outcomes. American journal of hematology Fang, H., Reichard, K. K., Rabe, K. G., Hanson, C. A., Call, T. G., Ding, W., Kenderian, S. S., Muchtar, E., Schwager, S. M., Leis, J. F., Chanan-Khan, A. A., Slager, S. L., Braggio, E., Smoley, S. A., Kay, N. E., Shanafelt, T. D., Van Dyke, D. L., Parikh, S. A. 2018

  Abstract

  The prevalence, clinicopathologic correlates, and outcomes of previously untreated chronic lymphocytic leukemia (CLL) patients with IGH-BCL2 and IGH-BCL3 translocations are not well known. Using the Mayo Clinic CLL database, we identified patients seen between 3/1/2002 and 9/30/2016 who had FISH testing performed within 3 years of CLL diagnosis. The prognostic profile, time to first therapy (TTT) and overall survival (OS) of patients with IGH-BCL2 and IGH-BCL3 translocation were compared to patients without these abnormalities (non-IGH group). Of 1684 patients who met the inclusion criteria, 38 (2.2%) had IGH-BCL2, and 16 (0.9%) had IGH-BCL3 translocation at diagnosis. Patients with IGH-BCL3 translocation were more likely to have high and very-high CLL-International Prognostic Index, compared to patients with IGH-BCL2 translocation and the non-IGH group. The 5-year probability of requiring therapy was significantly higher for IGH-BCL3 compared to IGH-BCL2 and non-IGH groups (84% vs. 33% vs. 29%, respectively, p<0.0001). The 5-year OS was significantly shorter for IGH-BCL3 compared to IGH-BCL2 and non-IGH groups (45% vs. 89% vs. 86%, respectively, p<0.0001). On multivariable analyses, IGH-BCL3 translocation was associated with a shorter TTT (hazard ratio (HR)=2.7; p=0.005) and shorter OS (HR=5.5; p<0.0001); IGH-BCL2 translocation did not impact TTT and OS. In conclusion, approximately 3% of all newly diagnosed CLL patients have either an IGH-BCL2 or IGH-BCL3 translocation. Patients with IGH-BCL3 translocations have a distinct prognostic profile and outcome. These results support the inclusion of an IGH probe during the routine evaluation of FISH abnormalities in newly diagnosed CLL. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ajh.25385

  View details for PubMedID 30575108

• Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL. The New England journal of medicine Woyach, J. A., Ruppert, A. S., Heerema, N. A., Zhao, W., Booth, A. M., Ding, W., Bartlett, N. L., Brander, D. M., Barr, P. M., Rogers, K. A., Parikh, S. A., Coutre, S., Hurria, A., Brown, J. R., Lozanski, G., Blachly, J. S., Ozer, H. G., Major-Elechi, B., Fruth, B., Nattam, S., Larson, R. A., Erba, H., Litzow, M., Owen, C., Kuzma, C., Abramson, J. S., Little, R. F., Smith, S. E., Stone, R. M., Mandrekar, S. J., Byrd, J. C. 2018

  Abstract

  BACKGROUND: Ibrutinib has been approved by the Food and Drug Administration for the treatment of patients with untreated chronic lymphocytic leukemia (CLL) since 2016 but has not been compared with chemoimmunotherapy. We conducted a phase 3 trial to evaluate the efficacy of ibrutinib, either alone or in combination with rituximab, relative to chemoimmunotherapy.METHODS: Patients 65 years of age or older who had untreated CLL were randomly assigned to receive bendamustine plus rituximab, ibrutinib, or ibrutinib plus rituximab. The primary end point was progression-free survival. The Alliance Data and Safety Monitoring Board made the decision to release the data after the protocol-specified efficacy threshold had been met.RESULTS: A total of 183 patients were assigned to receive bendamustine plus rituximab, 182 to receive ibrutinib, and 182 to receive ibrutinib plus rituximab. Median progression-free survival was reached only with bendamustine plus rituximab. The estimated percentage of patients with progression-free survival at 2 years was 74% with bendamustine plus rituximab and was higher with ibrutinib alone (87%; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.26 to 0.58; P<0.001) and with ibrutinib plus rituximab (88%; hazard ratio, 0.38; 95% CI, 0.25 to 0.59; P<0.001). There was no significant difference between the ibrutinib-plus-rituximab group and the ibrutinib group with regard to progression-free survival (hazard ratio, 1.00; 95% CI, 0.62 to 1.62; P=0.49). With a median follow-up of 38 months, there was no significant difference among the three treatment groups with regard to overall survival. The rate of grade 3, 4, or 5 hematologic adverse events was higher with bendamustine plus rituximab (61%) than with ibrutinib or ibrutinib plus rituximab (41% and 39%, respectively), whereas the rate of grade 3, 4, or 5 nonhematologic adverse events was lower with bendamustine plus rituximab (63%) than with the ibrutinib-containing regimens (74% with each regimen).CONCLUSIONS: Among older patients with untreated CLL, treatment with ibrutinib was superior to treatment with bendamustine plus rituximab with regard to progression-free survival. There was no significant difference between ibrutinib and ibrutinib plus rituximab with regard to progression-free survival. (Funded by the National Cancer Institute and Pharmacyclics; ClinicalTrials.gov number, NCT01886872 .).

  View details for PubMedID 30501481

• Clonal Hematopoiesis of Indeterminate Potential (CHIP) and Chronic Lymphocytic Leukemia (CLL) Driver Genes: Risk of CLL and Monoclonal B-Cell Lymphocytosis (MBL) Boddicker, N. J., O'Brien, D. R., Braggio, E., Achenbach, S. J., Chaffee, K. G., Norman, A. D., Vachon, C. M., Kabat, B., Call, T. G., Parikh, S. A., Leis, J. F., Ding, W., Muchtar, E., Cerhan, J. R., Shanafelt, T. D., Kay, N. E., Caporaso, N. E., Slager, S. L. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-117044

  View details for Web of Science ID 000454842800270

• Ibrutinib Alone or in Combination with Rituximab Produces Superior Progression Free Survival (PFS) Compared with Bendamustine Plus Rituximab in Untreated Older Patients with Chronic Lymphocytic Leukemia (CLL): Results of Alliance North American Intergroup Study A041202 Woyach, J. A., Ruppert, A. S., Heerema, N. A., Zhao, W., Booth, A. M., Ding, W., Bartlett, N. L., Brander, D. M., Barr, P., Rogers, K. A., Parikh, S. A., Coutre, S., Hurria, A., Lozanski, G., Nattam, S., Larson, R. A., Erba, H. P., Litzow, M. R., Owen, C., Atkins, J., Abramson, J. S., Little, R. F., Smith, S. E., Stone, R. M., Mandrekar, S. J., Byrd, J. C. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-116653

  View details for Web of Science ID 000454837600060

• Autoimmune cytopenias in patients with chronic lymphocytic leukaemia treated with ibrutinib in routine clinical practice at an academic medical centre BRITISH JOURNAL OF HAEMATOLOGY Hampel, P. J., Larson, M. C., Kabat, B., Call, T. G., Ding, W., Kenderian, S. S., Bowen, D., Boysen, J., Schwager, S. M., Leis, J. F., Chanan-Khan, A. A., Muchtar, E., Hanson, C. A., Slager, S. L., Kay, N. E., Chaffee, K. G., Shanafelt, T. D., Parikh, S. A. 2018; 183 (3): 421–27

  Abstract

  The effects of ibrutinib on the natural history of autoimmune cytopenias (AIC) among chronic lymphocytic leukaemia (CLL) patients treated in routine clinical practice require further investigation. Using the Mayo Clinical CLL Database, 193 CLL patients treated with ibrutinib between November 2013 and January 2017 outside the context of a clinical trial were identified; complete review of their medical records was performed for details of past history of AIC and treatment-emergent AIC. We identified 29/193 (15%) patients with history of AIC prior to ibrutinib start. Of 12 patients requiring AIC therapy at ibrutinib start, 8 (67%) were able to discontinue or de-escalate AIC treatment, and no patient had worsening of their AIC after initiating ibrutinib. Eleven (6%) patients developed treatment-emergent AIC after a median of 59 (range, 6-319) days following the initiation of ibrutinib, 7 of whom (64%) were able to continue ibrutinib. Overall and event-free survival from time of ibrutinib start were not significantly different between patients with history of AIC and those with no history of AIC. Treatment-emergent AIC were seen exclusively in patients with unmutated IGHV and were associated with a shorter EFS. These results suggest a low rate of treatment-emergent AIC and improvement in patients with existing AIC.

  View details for PubMedID 30117139

  View details for PubMedCentralID PMC6234062

• Outcomes of a large cohort of individuals with clinically ascertained high-count monoclonal B-cell lymphocytosis HAEMATOLOGICA Parikh, S. A., Chaffee, K. G., Larson, M. C., Hampel, P. J., Call, T. G., Ding, W., Kenderian, S. S., Leis, J. F., Chanan-Khan, A. A., Conte, M. J., Bowen, D., Schwager, S. M., Slager, S. L., Hanson, C. A., Kay, N. E., Shanafelt, T. D. 2018; 103 (6): E237–E240

  View details for PubMedID 29419435

• Rapid progression of disease following ibrutinib discontinuation in patients with chronic lymphocytic leukemia. Hampel, P., Chaffee, K. G., Ding, W., Call, T., Kenderian, S., Muchtar, E., Leis, J., Chanan-Khan, A., Bowen, D., Fonder, A. L., Schwager, S. M., Slager, S. L., Shanafelt, T. D., Kay, N. E., Parikh, S. AMER SOC CLINICAL ONCOLOGY. 2018

  View details for DOI 10.1200/JCO.2018.36.15_suppl.7525

  View details for Web of Science ID 000442916002595

• Cumulative experience and long term follow-up of pentostatin-based chemoimmunotherapy trials for patients with chronic lymphocytic leukemia EXPERT REVIEW OF HEMATOLOGY Kay, N. E., LaPlant, B. R., Pettinger, A. M., Call, T. G., Leis, J. F., Ding, W., Parikh, S. A., Conte, M. J., Bowen, D. A., Shanafelt, T. D. 2018; 11 (4): 337–49

  Abstract

  7 regimens of pentostatin based chemoimmunotherapy (CIT) for progressive previously untreated CLL primarily with long term follow-up to update both efficacy and toxicity.Prognostic markers including assessment of IGVH and FISH status were done on all. Response rates and 95% binomial confidence intervals were calculated for each regimen and in the combined cohort. Overall survival and treatment-free survival were evaluated using Kaplan-Meier methods.The initial CIT trial was pentostatin (2 mgs/m2), cyclophosphamide (600 mg/m2) and rituximab (PCR) but subsequent P based CIT trials with modifications in subsequent trials. The cohort (n = 288) included 52% with unmutated IGVH status and del17p (4.5%) and del11q (14.9%). Toxicity profiles were primarily hematologic and no patient has developed MDS or AML after a median follow-up of 6.4 years. The overall response rate across all trials was found to be over 90% with a 41% complete response rate. We validated that the CLL IPI model segregates progressive CLL patients into 4 risk groups associated with OS and TFS.The high overall and complete response levels in favorable genetic risk CLL along with favorable toxicity profiles provide rationale for consideration of a PC based strategy for previously untreated progressive CLL.

  View details for PubMedID 29460654