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Dose-adjusted EPOCH chemotherapy with bortezomib and raltegravir for human T-cell leukemia virus-associated adult T-cell leukemia lymphoma

Dose-adjusted EPOCH chemotherapy with bortezomib and raltegravir for human T-cell leukemia... OPEN Citation: Blood Cancer Journal (2016) 6, e408; doi:10.1038/bcj.2016.21 www.nature.com/bcj LETTER TO THE EDITOR Dose-adjusted EPOCH chemotherapy with bortezomib and raltegravir for human T-cell leukemia virus-associated adult T-cell leukemia lymphoma Blood Cancer Journal (2016) 6, e408; doi:10.1038/bcj.2016.21; those expected for DA-EPOCH alone (Figure 1b, Supplementary Table S1). published online 25 March 2016 Three subjects achieved complete remission and eight subjects achieved partial remission, with similar response rates (67%) in acute and lymphoma ATLL (Figure 1a). With follow-up ‘Acute’ and ‘lymphoma’ subtypes are the most common forms of 42 years for all subjects, median progression-free and overall of human T-cell leukemia virus (HTLV)-associated adult T-cell survival were 5.8 and 6.2 mos, respectively, with four subjects leukemia lymphoma (ATLL), with median survivals of only still alive (Figure 1c). The responses in this study were similar to 8–12 months. Treatment with interferon, zidovudine, arsenic, those of a previous DA-EPOCH trial without bortezomib and mogamulizumab, multiagent chemotherapy and allogeneic raltegravir, suggesting that NFκB target genes and virus stem cell transplants yielded positive results, but most replication were incompletely inhibited, or they did not individuals with ATLL succumb to their disease. In our previous contribute to chemotherapy resistance. In the current study, multicenter trial of 19 subjects, using dose-adjusted infusional no patients had dose-limiting toxicity, likely due to the lower chemotherapy (DA-EPOCH) followed by maintenance interferon dose of cyclophosphamide at treatment initiation. Similar and zidovudine, there were two complete remissions, response rates were reported with other chemotherapy four subjects with early severe toxicity and an overall response 5,6 approaches. rate of 58%. Half of the evaluable subjects manifested Proviral loads at baseline were 0.368 copies/peripheral blood significantly increased viral gene expression with disease mononuclear cell (PBMC) for acute ATLL subjects and 0.216 progression and new integration sites were identified in most copies/PBMC for lymphoma patients (P = 0.002), but were similar subjects. The current study was designed to test the tolerability for responders (mean 0.372) and nonresponders (mean 0.0417, and efficacy of a regimen with: (1) decreased dose intensity P = 0.99). However, proviral loads were lower at study completion during the initial cycles of therapy, (2) addition of bortezomib to for responders (mean 0.0128) compared with nonresponders block NFκB activation and (3) incorporate the antiviral raltegravir (mean 0.033, Po0.0001). (previously shown to block HTLV-1 replication) (Supplementary Levels in PBMCs were determined for tax and hbz messenger Protocol File). In addition, we assessed viral and cellular RNAs, encoded from the plus and minus viral strands, parameters of response. respectively. Baseline tax messenger RNA levels for acute Our phase 1/2 trial enrolled consenting subjects with ATLL subjects were 0.04 copies, and for lymphoma ATLL, 2.0 untreated (n = 14) or previously treated (n =4) acute (n =6) or copies/100 copies hprt messenger RNA (range 0–13.4, P = 0.33). lymphoma ATLL (n = 12), adequate hematologic, renal and The mean hbz messenger RNA levels at baseline were 98.5 hepatic function, and Karnofsky performance score 450 copies for acute ATLL and 8.7 copies/100 copies hprt messenger (Figure 1a). Subjects were enrolled at six centers from 2011 to RNA for patients with lymphoma (P = 0.016). There was 2013 and were treated with DA-EPOCH with intravenous no difference in baseline hbz RNA levels between responders bortezomib (d1 and 4, 1.0 mg/m ), and daily raltegravir (mean 37.0 copies) and nonresponders (mean 41.9 copies, (400 mg bid) was initiated with cycle 2 therapy. Patients P = 0.11), but lower levels at study conclusion in responders received up to six 21-day cycles of treatment unless they had (mean 7.33 copies) than nonresponders (mean 35.7 copies, evidence of disease progression or dose-limiting toxicity. Po0.0001). Disease staging and viral studies were performed at baseline, HTLV-1 integrase sequences at baseline and at the end of the just before cycles 3 and 5, and after completion of treatment. study exhibited o1% intra- and interpatient nucleotide Viral DNA load, tax and hbz RNA levels were quantified by divergence. Only three residues differed from the consensus digital droplet polymerase chain reaction. Viral sequences HTLV-1 sequence, in agreement with the high levels of sequence were determined by Illumina HiSeq-2500 (San Diego, CA, USA). conservation reported from this virus. Only one residue (E100K) Thesamplesizewas based onatwo-stage Simon’sdesign for a exhibited an increased frequency at the end of the study (0.67) response rate of at least 30%, with a significance level of 10% and a power of 80%. The Kaplan–Meier method was used to compared with the baseline (0.46), corresponding to determine duration of response and survival. Correlations of a raltegravir-resistant mutation in HIV-1 (E92Q; http://hivdb. viral parameters with response were assessed by two-sided stanford.edu/DR/INIResiNote.html). Sequence analysis of inte- Student’s t-tests (see Supplementary Methods). gration sites revealed 1–5 clonal integration sites in each The mean age of subjects was 52 years and all but three US individual and no significant differences between baseline and subjects were born in the Caribbean (Figure 1a). At baseline, all end of the study samples. Thus, in contrast to our previous trial but one subject had stage IV disease, nine had hypercalcemia, lacking antivirals during induction chemotherapy, the current 16 had elevated lactate dehydrogenase levels, one had study subjects exhibited little evidence of active virus thrombocytopenia and six patients had hypoalbuminemia. replication. The mean absolute lymphocyte count was 38 900/mm for RNAseq analysis was performed on PBMC samples obtained at acute ATLL patients and 1610/mm for those with lymphoma. baseline and end point from subjects with acute ATLL including Patients received on average, 4.5 cycles of DA-EPOCH-bortezo- two responders and two nonresponders who had 66–99% CD4+ mib, with raltegravir. Complications of therapy were similar to lymphocytes/PBMC at baseline. Effects on NFκB target genes are Letter to the Editor Baseline Data on Patients and Clinical Responses (*, P < 0.05) ATLL Subtype - Mean values (range) Acute ATLL Lymphoma ATLL Number of males / females 2 / 4 2 / 10 Age 51.5 (38-70) 56 (36-76) Number who failed prior regimens 13 Baseline Karnofsky Performance Score 80 (60-100) 86 (50-100) Birthplace 3 J, 1 D, 1 B, 1 U 5 J, 3 H, 1 V, 2 U, 1 A Baseline Absolute Lymphocyte Count * 38,900 (4,300-124,000) 1,610 (700-3700) Baseline CD3-Positive Cell Count * 15,940 (3,800-119,000) 940 (270-3100) Baseline Lactate Dehydrogenase (u/L) 460 (390-1500) 465 (220-1600) Baseline Calcium (mg/dl) 14.5 (9-18) 11.6 (8.3-15.8) Positive Baseline Bone Marrow Biopsies 5 of 5 6 of 11 Number of Treatment Cycles 4.5 4.5 Baseline HTLV-1 Proviral Load 0.368 (0.055-0.150) 0.216 (0.0011-0.061) (copies / PBMC) Baseline Tax RNA Level 0.04 (0-0.26) 1.98 (0-13.4) (copies per 100 hprt copies) * Baseline HBZ RNA Levels 98.5 (55.7-176.5) 8.7 (0-44.2) (copies per 100 hprt copies) * Number with Best Responses: Complete Response 1 2 Partial Response 3 6 Stable Disease 1 2 Progressive Disease 1 2 Response Rate (PR + CR / Total) 67% 67% Diagnostic criteria for ATLL subtypes: anti-HTLV-1 antibody pos; ALC<4000, Abn T lymphocytes<1%, and no flower cells in peripheral blood and proven lymphadenopathy for lymphoma Prior regimens included AZT/interferon, bexarotene, ultraviolet B, CHOP A, Antigua; D, Dominican Republic; H, Haiti; J, Jamaica; U, USA; V, Virgin Islands Serious adverse events: 1 grade 5 sepsis at time of relapse, 14 grade 4 toxicities (5 neutropenias, 4 thrombocytopenias, 2 leukopenias, 1 each with sepsis and neutropenic fever), and 38 grade 3 toxicities (11 hematologic, 5 gastrointestinal, 5 metabolic, 2 pulmonary, 2 infectious). Progression-free and Overall Survival Results No. 18 4 1 No. 12 11 3 1 at Risk at Risk Figure 1. Baseline data, regimen toxicities and responses for patients. (a) Baseline clinical and virological data are provided for the 18 patients in the clinical trial, subdivided by acute versus lymphoma ATLL subtypes. (b) Serious adverse events during clinical trial participation are shown for these subjects. (c) Progression-free survival is shown for responders, as well as overall survival for all clinical trial participants. ALC, absolute lymphocyte count; AZT, azidothymidine; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CR, complete response; PR, partial response. shown in Supplementary Figures S1 and 2. The most significant correlated with CD101 expression in most ATLL samples difference between these groups was the expression of the Src (Supplementary Figure S4). CD101 is a repressor of T cell receptor signaling and T-cell proliferation. This finding is consistent family tyrosine kinase Blk (Figure 2). This result was surprising since Blk is predominantly expressed in B cells. However, a subset with the high rates of gain-of-function mutations in genes of the 52 primary ATLL samples from a separate patient cohort encoding T cell receptor-pathway proteins (unpublished data 8 12 also express elevated Blk (Supplementary Figure S3). Blk is and Kataoka et al. ). constitutively active in cutaneous T-cell lymphoma and can be In conclusion, the current regimen was well-tolerated. effectively targeted with dasatinib. Blk expression is inversely Changes in proviral load and hbz RNA expression provide Blood Cancer Journal Letter to the Editor Division of Oncology, Department of Medicine, Washington Responders Non-Responders University School of Medicine, St Louis, MO, USA; Department of Genetics, Washington University School of Medicine, St Louis, MO, USA; Viral Immunology Section, Neuroimmunology and Neurovirology Division, NINDS, NIH, Bethesda, MD, USA; Lymphoma Service, Memorial Sloan Kettering Cancer Center, 0.1 A1 B1 C1 D1 New York, NY, USA; Division of Hematology–Oncology, Department of Medicine, 0.01 BLK Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA; CADM1 Therapy Division of Hematology–Oncology, Department of Medicine, CD25 University of Miami School of Medicine, Miami, FL, USA; CD4 Division of Hematologic Malignancies, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA and 100 CD45 Division of Hematology–Oncology, Department of Medicine, Columbia University Medical Center, New York, NY, USA E-mail: lratner@dom.wustl.edu Current address: Department of Hematology/Oncology, Fox Chase School of Medicine, Philadelphia, PA, USA Current address: Division of Hematology and Medical Oncology, 0.1 Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA 0.01 Current address: Division of Hematology/Medical Oncology, A2 B2 C2 D2 Department of Medicine, Weill Cornell School of Medicine, New York, NY, USA Figure 2. Blk expression is elevated in ATLL nonresponders. RNAseq was performed on RNA obtained from PBMCs collected from four patients (A, B, C and D) with acute disease REFERENCES before (upper graph) and after (lower graph) treatment with DA-EPOCH-based chemotherapy combined with borte- 1 Katsuya H, Ishitsuka K, Utsunomiya A, Hanada S, Eto T, Moriuchi Y et al. zomib and raltegravir. Average reads per kilobase of transcript Treatment and survival among 1594 patients with ATL. Blood 2015; 126: per million mapped reads (RPKM) values normalized to patient 2570–2577. Abeforetherapy (A1) areshown forprotein-coding 2 Ratner L, Harrington W, Feng X, Grant C, Jacobson S, Noy A et al. Human T cell transcripts from the five genes indicated. CADM1 and CD25 leukemia virus reactivation with progression of adult T-cell leukemia-lymphoma. are markers for ATLL and CD45 (PTPRC) is a panleukocyte AIDS Malignancy Consortium. PLoS One 2009; 4: e4420. marker. 3 Seegulam ME, Ratner L. Integrase inhibitors effective against human T-cell leukemia virus type 1. Antimicrob Agents Chemother 2011; 55: 2011–2017. 4 Brunetto GS, Massoud R, Leibovitch EC, Caruso B, Johnson K, Ohayon J et al. Digital droplet PCR (ddPCR) for the precise quantification of human T-lympho- tropic virus 1 proviral loads in peripheral blood and cerebrospinal fluid of potential markers of antitumor response. Concurrent antiviral HAM/TSP patients and identification of viral mutations. J Neurovirol 2014; 20: integrase inhibitor therapy was well-tolerated and limited 341–351. virus replication. Repression of NFκB through proteasome 5 Ishida T, Jo T, Takemoto S, Suzushima H, Uozumi K, Yamamoto K et al. inhibition targets a key pathway responsible for apoptosis Dose-intensified chemotherapy alone or in combination with mogamulizumab in resistance. Expression of Blk and reduction of CD101 in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: a randomized subjects that failed to respond to therapy suggests a mechanism phase II study. Br J Haematol 2015; 169: 672–682. and a therapeutic target for future trials. Allogeneic stem cell 6 Tsukasaki K, Utsonomiya A, Fukuda H, Shibata T, Fukushima T, Takatsuka Y et al. transplantation is an effective consolidation therapy for ATLL VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lym- phoma: Japan Clinical Oncology Group Study JCOG9801. J Clin Oncol 2007; 25: and was utilized in three patients on the current trial. 5458–5864. Although response rates in the current trial were short-lived, 7 Cassar O, Einsiedel L, Afonso PV, Gessain A. Human T-cell lymphotropic virus type this therapy could serve as a bridge to allogeneic stem cell 1 subtype C molecular variants among indigenous Australians: new insights into transplantation to induce more long-lived responses. Future the molecular epidemiology of HTLV-1 in Australo-Melanesia. PLoS Negl Trop Dis studies are focused on other immunotherapy approaches for 2013; 26: e2418. this disease, such as therapeutic vaccines, CAR T cells or immune 8 Yamagishi M, Nakano K, Miyake A, Yamochi T, Kagami Y, Tsutsumi A et al. checkpoint therapies. Polycomb-mediated loss of miR-31 activated NIK-dependent NF-kB pathway in adult T cell leukemia and other cancers. Cancer Cell 2012; 21: 121–136. CONFLICT OF INTEREST 9 Krejsgaard T, CSV-K CS, Woetmann A, Kneitz H, Eriksen KW, Lovato P et al. Ectopic expression of B-lymphoid kinase in cutaneous T-cell lymphoma. Blood 2009; 113: The authors declare no conflict of interest. 5896–5904. 10 Petersen DL, Krejsgaard T, Berthelsen J, Fredholm S, Willerslev-Olsen A, Sibbesen NA et al. B-lymphoid tyrosine kinase (Blk) is an oncogene and a potential target ACKNOWLEDGEMENTS for therapy with dasatinib in cutaneous T-cell lymphoma (CTCL). Leukemia 2015; The study was funded by grants LLS 6067-10, CA 63417, CA10073, CA94056 28: 2109–2112. and LRF307181203. Drugs were provided by Millenium Inc and Merck-Sharp- 11 Soares LR, Tsavaler L, Rivas A, Engleman EG. V7 (CD101) ligation inhibits TCR/CD3- Dohne Inc. induced IL-2 production by blocking Ca2+ flux and nuclear factor of activated T cell nuclear translocation. J Immunol 1998; 161:209–217. 1 1 2 3 4 5,9 L Ratner , D Rauch , H Abel , B Caruso , A Noy , SK Barta , 12 Kataoka K, Nagata Y, Kitanaka A, Shiraishi Y, Shimamura T, Yasunaga J et al. 5,10 6 7 8,11 1 S Parekh , JC Ramos , R Ambinder , A Phillips , J Harding , Integrated molecular analysis of adult T-cell leukemia/lymphoma. Nat Genet 2015; 1 1 3 HH Baydoun , X Cheng and S Jacobson 47: 1304–1315. Blood Cancer Journal RPKM/A1 RPKM/A1 Letter to the Editor 13 Bernal-Mizrachi L, Lovly CM, Ratner L. The role of nuclear factor kB-1 This work is licensed under a Creative Commons Attribution 4.0 and -2-mediated resistance to apoptosis in lymphomas. Proc Natl Acad Sci USA International License. The images or other third party material in this 2006; 103: 9220–9225. article are included in the article’s Creative Commons license, unless indicated 14 Utsunomiya A, Choi I, Chihara D, Seto M. Recent advances in the treatment of otherwise in the credit line; if the material is not included under the Creative Commons adult T-cell leukemia-lymphomas. Cancer Sci 2015; 106:344–351. license, users will need to obtain permission from the license holder to reproduce the 15 Kline J, Bishop MR. Update on checkpoint blockade therapy for lymphoma. material. To view a copy of this license, visit http://creativecommons.org/licenses/ J Immunother Cancer 2015; 3:33. by/4.0/ Supplementary Information accompanies this paper on Blood Cancer Journal website (http://www.nature.com/bcj) Blood Cancer Journal http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Blood Cancer Journal Springer Journals

Dose-adjusted EPOCH chemotherapy with bortezomib and raltegravir for human T-cell leukemia virus-associated adult T-cell leukemia lymphoma

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Biomedicine; Biomedicine, general; Cancer Research; Oncology; Hematology
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OPEN Citation: Blood Cancer Journal (2016) 6, e408; doi:10.1038/bcj.2016.21 www.nature.com/bcj LETTER TO THE EDITOR Dose-adjusted EPOCH chemotherapy with bortezomib and raltegravir for human T-cell leukemia virus-associated adult T-cell leukemia lymphoma Blood Cancer Journal (2016) 6, e408; doi:10.1038/bcj.2016.21; those expected for DA-EPOCH alone (Figure 1b, Supplementary Table S1). published online 25 March 2016 Three subjects achieved complete remission and eight subjects achieved partial remission, with similar response rates (67%) in acute and lymphoma ATLL (Figure 1a). With follow-up ‘Acute’ and ‘lymphoma’ subtypes are the most common forms of 42 years for all subjects, median progression-free and overall of human T-cell leukemia virus (HTLV)-associated adult T-cell survival were 5.8 and 6.2 mos, respectively, with four subjects leukemia lymphoma (ATLL), with median survivals of only still alive (Figure 1c). The responses in this study were similar to 8–12 months. Treatment with interferon, zidovudine, arsenic, those of a previous DA-EPOCH trial without bortezomib and mogamulizumab, multiagent chemotherapy and allogeneic raltegravir, suggesting that NFκB target genes and virus stem cell transplants yielded positive results, but most replication were incompletely inhibited, or they did not individuals with ATLL succumb to their disease. In our previous contribute to chemotherapy resistance. In the current study, multicenter trial of 19 subjects, using dose-adjusted infusional no patients had dose-limiting toxicity, likely due to the lower chemotherapy (DA-EPOCH) followed by maintenance interferon dose of cyclophosphamide at treatment initiation. Similar and zidovudine, there were two complete remissions, response rates were reported with other chemotherapy four subjects with early severe toxicity and an overall response 5,6 approaches. rate of 58%. Half of the evaluable subjects manifested Proviral loads at baseline were 0.368 copies/peripheral blood significantly increased viral gene expression with disease mononuclear cell (PBMC) for acute ATLL subjects and 0.216 progression and new integration sites were identified in most copies/PBMC for lymphoma patients (P = 0.002), but were similar subjects. The current study was designed to test the tolerability for responders (mean 0.372) and nonresponders (mean 0.0417, and efficacy of a regimen with: (1) decreased dose intensity P = 0.99). However, proviral loads were lower at study completion during the initial cycles of therapy, (2) addition of bortezomib to for responders (mean 0.0128) compared with nonresponders block NFκB activation and (3) incorporate the antiviral raltegravir (mean 0.033, Po0.0001). (previously shown to block HTLV-1 replication) (Supplementary Levels in PBMCs were determined for tax and hbz messenger Protocol File). In addition, we assessed viral and cellular RNAs, encoded from the plus and minus viral strands, parameters of response. respectively. Baseline tax messenger RNA levels for acute Our phase 1/2 trial enrolled consenting subjects with ATLL subjects were 0.04 copies, and for lymphoma ATLL, 2.0 untreated (n = 14) or previously treated (n =4) acute (n =6) or copies/100 copies hprt messenger RNA (range 0–13.4, P = 0.33). lymphoma ATLL (n = 12), adequate hematologic, renal and The mean hbz messenger RNA levels at baseline were 98.5 hepatic function, and Karnofsky performance score 450 copies for acute ATLL and 8.7 copies/100 copies hprt messenger (Figure 1a). Subjects were enrolled at six centers from 2011 to RNA for patients with lymphoma (P = 0.016). There was 2013 and were treated with DA-EPOCH with intravenous no difference in baseline hbz RNA levels between responders bortezomib (d1 and 4, 1.0 mg/m ), and daily raltegravir (mean 37.0 copies) and nonresponders (mean 41.9 copies, (400 mg bid) was initiated with cycle 2 therapy. Patients P = 0.11), but lower levels at study conclusion in responders received up to six 21-day cycles of treatment unless they had (mean 7.33 copies) than nonresponders (mean 35.7 copies, evidence of disease progression or dose-limiting toxicity. Po0.0001). Disease staging and viral studies were performed at baseline, HTLV-1 integrase sequences at baseline and at the end of the just before cycles 3 and 5, and after completion of treatment. study exhibited o1% intra- and interpatient nucleotide Viral DNA load, tax and hbz RNA levels were quantified by divergence. Only three residues differed from the consensus digital droplet polymerase chain reaction. Viral sequences HTLV-1 sequence, in agreement with the high levels of sequence were determined by Illumina HiSeq-2500 (San Diego, CA, USA). conservation reported from this virus. Only one residue (E100K) Thesamplesizewas based onatwo-stage Simon’sdesign for a exhibited an increased frequency at the end of the study (0.67) response rate of at least 30%, with a significance level of 10% and a power of 80%. The Kaplan–Meier method was used to compared with the baseline (0.46), corresponding to determine duration of response and survival. Correlations of a raltegravir-resistant mutation in HIV-1 (E92Q; http://hivdb. viral parameters with response were assessed by two-sided stanford.edu/DR/INIResiNote.html). Sequence analysis of inte- Student’s t-tests (see Supplementary Methods). gration sites revealed 1–5 clonal integration sites in each The mean age of subjects was 52 years and all but three US individual and no significant differences between baseline and subjects were born in the Caribbean (Figure 1a). At baseline, all end of the study samples. Thus, in contrast to our previous trial but one subject had stage IV disease, nine had hypercalcemia, lacking antivirals during induction chemotherapy, the current 16 had elevated lactate dehydrogenase levels, one had study subjects exhibited little evidence of active virus thrombocytopenia and six patients had hypoalbuminemia. replication. The mean absolute lymphocyte count was 38 900/mm for RNAseq analysis was performed on PBMC samples obtained at acute ATLL patients and 1610/mm for those with lymphoma. baseline and end point from subjects with acute ATLL including Patients received on average, 4.5 cycles of DA-EPOCH-bortezo- two responders and two nonresponders who had 66–99% CD4+ mib, with raltegravir. Complications of therapy were similar to lymphocytes/PBMC at baseline. Effects on NFκB target genes are Letter to the Editor Baseline Data on Patients and Clinical Responses (*, P < 0.05) ATLL Subtype - Mean values (range) Acute ATLL Lymphoma ATLL Number of males / females 2 / 4 2 / 10 Age 51.5 (38-70) 56 (36-76) Number who failed prior regimens 13 Baseline Karnofsky Performance Score 80 (60-100) 86 (50-100) Birthplace 3 J, 1 D, 1 B, 1 U 5 J, 3 H, 1 V, 2 U, 1 A Baseline Absolute Lymphocyte Count * 38,900 (4,300-124,000) 1,610 (700-3700) Baseline CD3-Positive Cell Count * 15,940 (3,800-119,000) 940 (270-3100) Baseline Lactate Dehydrogenase (u/L) 460 (390-1500) 465 (220-1600) Baseline Calcium (mg/dl) 14.5 (9-18) 11.6 (8.3-15.8) Positive Baseline Bone Marrow Biopsies 5 of 5 6 of 11 Number of Treatment Cycles 4.5 4.5 Baseline HTLV-1 Proviral Load 0.368 (0.055-0.150) 0.216 (0.0011-0.061) (copies / PBMC) Baseline Tax RNA Level 0.04 (0-0.26) 1.98 (0-13.4) (copies per 100 hprt copies) * Baseline HBZ RNA Levels 98.5 (55.7-176.5) 8.7 (0-44.2) (copies per 100 hprt copies) * Number with Best Responses: Complete Response 1 2 Partial Response 3 6 Stable Disease 1 2 Progressive Disease 1 2 Response Rate (PR + CR / Total) 67% 67% Diagnostic criteria for ATLL subtypes: anti-HTLV-1 antibody pos; ALC<4000, Abn T lymphocytes<1%, and no flower cells in peripheral blood and proven lymphadenopathy for lymphoma Prior regimens included AZT/interferon, bexarotene, ultraviolet B, CHOP A, Antigua; D, Dominican Republic; H, Haiti; J, Jamaica; U, USA; V, Virgin Islands Serious adverse events: 1 grade 5 sepsis at time of relapse, 14 grade 4 toxicities (5 neutropenias, 4 thrombocytopenias, 2 leukopenias, 1 each with sepsis and neutropenic fever), and 38 grade 3 toxicities (11 hematologic, 5 gastrointestinal, 5 metabolic, 2 pulmonary, 2 infectious). Progression-free and Overall Survival Results No. 18 4 1 No. 12 11 3 1 at Risk at Risk Figure 1. Baseline data, regimen toxicities and responses for patients. (a) Baseline clinical and virological data are provided for the 18 patients in the clinical trial, subdivided by acute versus lymphoma ATLL subtypes. (b) Serious adverse events during clinical trial participation are shown for these subjects. (c) Progression-free survival is shown for responders, as well as overall survival for all clinical trial participants. ALC, absolute lymphocyte count; AZT, azidothymidine; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CR, complete response; PR, partial response. shown in Supplementary Figures S1 and 2. The most significant correlated with CD101 expression in most ATLL samples difference between these groups was the expression of the Src (Supplementary Figure S4). CD101 is a repressor of T cell receptor signaling and T-cell proliferation. This finding is consistent family tyrosine kinase Blk (Figure 2). This result was surprising since Blk is predominantly expressed in B cells. However, a subset with the high rates of gain-of-function mutations in genes of the 52 primary ATLL samples from a separate patient cohort encoding T cell receptor-pathway proteins (unpublished data 8 12 also express elevated Blk (Supplementary Figure S3). Blk is and Kataoka et al. ). constitutively active in cutaneous T-cell lymphoma and can be In conclusion, the current regimen was well-tolerated. effectively targeted with dasatinib. Blk expression is inversely Changes in proviral load and hbz RNA expression provide Blood Cancer Journal Letter to the Editor Division of Oncology, Department of Medicine, Washington Responders Non-Responders University School of Medicine, St Louis, MO, USA; Department of Genetics, Washington University School of Medicine, St Louis, MO, USA; Viral Immunology Section, Neuroimmunology and Neurovirology Division, NINDS, NIH, Bethesda, MD, USA; Lymphoma Service, Memorial Sloan Kettering Cancer Center, 0.1 A1 B1 C1 D1 New York, NY, USA; Division of Hematology–Oncology, Department of Medicine, 0.01 BLK Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA; CADM1 Therapy Division of Hematology–Oncology, Department of Medicine, CD25 University of Miami School of Medicine, Miami, FL, USA; CD4 Division of Hematologic Malignancies, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA and 100 CD45 Division of Hematology–Oncology, Department of Medicine, Columbia University Medical Center, New York, NY, USA E-mail: lratner@dom.wustl.edu Current address: Department of Hematology/Oncology, Fox Chase School of Medicine, Philadelphia, PA, USA Current address: Division of Hematology and Medical Oncology, 0.1 Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA 0.01 Current address: Division of Hematology/Medical Oncology, A2 B2 C2 D2 Department of Medicine, Weill Cornell School of Medicine, New York, NY, USA Figure 2. Blk expression is elevated in ATLL nonresponders. RNAseq was performed on RNA obtained from PBMCs collected from four patients (A, B, C and D) with acute disease REFERENCES before (upper graph) and after (lower graph) treatment with DA-EPOCH-based chemotherapy combined with borte- 1 Katsuya H, Ishitsuka K, Utsunomiya A, Hanada S, Eto T, Moriuchi Y et al. zomib and raltegravir. Average reads per kilobase of transcript Treatment and survival among 1594 patients with ATL. Blood 2015; 126: per million mapped reads (RPKM) values normalized to patient 2570–2577. Abeforetherapy (A1) areshown forprotein-coding 2 Ratner L, Harrington W, Feng X, Grant C, Jacobson S, Noy A et al. Human T cell transcripts from the five genes indicated. CADM1 and CD25 leukemia virus reactivation with progression of adult T-cell leukemia-lymphoma. are markers for ATLL and CD45 (PTPRC) is a panleukocyte AIDS Malignancy Consortium. PLoS One 2009; 4: e4420. marker. 3 Seegulam ME, Ratner L. Integrase inhibitors effective against human T-cell leukemia virus type 1. Antimicrob Agents Chemother 2011; 55: 2011–2017. 4 Brunetto GS, Massoud R, Leibovitch EC, Caruso B, Johnson K, Ohayon J et al. Digital droplet PCR (ddPCR) for the precise quantification of human T-lympho- tropic virus 1 proviral loads in peripheral blood and cerebrospinal fluid of potential markers of antitumor response. Concurrent antiviral HAM/TSP patients and identification of viral mutations. J Neurovirol 2014; 20: integrase inhibitor therapy was well-tolerated and limited 341–351. virus replication. Repression of NFκB through proteasome 5 Ishida T, Jo T, Takemoto S, Suzushima H, Uozumi K, Yamamoto K et al. inhibition targets a key pathway responsible for apoptosis Dose-intensified chemotherapy alone or in combination with mogamulizumab in resistance. Expression of Blk and reduction of CD101 in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: a randomized subjects that failed to respond to therapy suggests a mechanism phase II study. Br J Haematol 2015; 169: 672–682. and a therapeutic target for future trials. Allogeneic stem cell 6 Tsukasaki K, Utsonomiya A, Fukuda H, Shibata T, Fukushima T, Takatsuka Y et al. transplantation is an effective consolidation therapy for ATLL VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lym- phoma: Japan Clinical Oncology Group Study JCOG9801. J Clin Oncol 2007; 25: and was utilized in three patients on the current trial. 5458–5864. Although response rates in the current trial were short-lived, 7 Cassar O, Einsiedel L, Afonso PV, Gessain A. Human T-cell lymphotropic virus type this therapy could serve as a bridge to allogeneic stem cell 1 subtype C molecular variants among indigenous Australians: new insights into transplantation to induce more long-lived responses. Future the molecular epidemiology of HTLV-1 in Australo-Melanesia. PLoS Negl Trop Dis studies are focused on other immunotherapy approaches for 2013; 26: e2418. this disease, such as therapeutic vaccines, CAR T cells or immune 8 Yamagishi M, Nakano K, Miyake A, Yamochi T, Kagami Y, Tsutsumi A et al. checkpoint therapies. Polycomb-mediated loss of miR-31 activated NIK-dependent NF-kB pathway in adult T cell leukemia and other cancers. Cancer Cell 2012; 21: 121–136. CONFLICT OF INTEREST 9 Krejsgaard T, CSV-K CS, Woetmann A, Kneitz H, Eriksen KW, Lovato P et al. Ectopic expression of B-lymphoid kinase in cutaneous T-cell lymphoma. Blood 2009; 113: The authors declare no conflict of interest. 5896–5904. 10 Petersen DL, Krejsgaard T, Berthelsen J, Fredholm S, Willerslev-Olsen A, Sibbesen NA et al. B-lymphoid tyrosine kinase (Blk) is an oncogene and a potential target ACKNOWLEDGEMENTS for therapy with dasatinib in cutaneous T-cell lymphoma (CTCL). Leukemia 2015; The study was funded by grants LLS 6067-10, CA 63417, CA10073, CA94056 28: 2109–2112. and LRF307181203. Drugs were provided by Millenium Inc and Merck-Sharp- 11 Soares LR, Tsavaler L, Rivas A, Engleman EG. V7 (CD101) ligation inhibits TCR/CD3- Dohne Inc. induced IL-2 production by blocking Ca2+ flux and nuclear factor of activated T cell nuclear translocation. J Immunol 1998; 161:209–217. 1 1 2 3 4 5,9 L Ratner , D Rauch , H Abel , B Caruso , A Noy , SK Barta , 12 Kataoka K, Nagata Y, Kitanaka A, Shiraishi Y, Shimamura T, Yasunaga J et al. 5,10 6 7 8,11 1 S Parekh , JC Ramos , R Ambinder , A Phillips , J Harding , Integrated molecular analysis of adult T-cell leukemia/lymphoma. Nat Genet 2015; 1 1 3 HH Baydoun , X Cheng and S Jacobson 47: 1304–1315. Blood Cancer Journal RPKM/A1 RPKM/A1 Letter to the Editor 13 Bernal-Mizrachi L, Lovly CM, Ratner L. The role of nuclear factor kB-1 This work is licensed under a Creative Commons Attribution 4.0 and -2-mediated resistance to apoptosis in lymphomas. Proc Natl Acad Sci USA International License. The images or other third party material in this 2006; 103: 9220–9225. article are included in the article’s Creative Commons license, unless indicated 14 Utsunomiya A, Choi I, Chihara D, Seto M. Recent advances in the treatment of otherwise in the credit line; if the material is not included under the Creative Commons adult T-cell leukemia-lymphomas. Cancer Sci 2015; 106:344–351. license, users will need to obtain permission from the license holder to reproduce the 15 Kline J, Bishop MR. Update on checkpoint blockade therapy for lymphoma. material. To view a copy of this license, visit http://creativecommons.org/licenses/ J Immunother Cancer 2015; 3:33. by/4.0/ Supplementary Information accompanies this paper on Blood Cancer Journal website (http://www.nature.com/bcj) Blood Cancer Journal

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Published: Mar 25, 2016

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