93 results on '"kalakonda, N."'
Search Results
2. Effect of Prior Therapy and Disease Refractoriness on the Efficacy and Safety of Oral Selinexor in Patients with Diffuse Large B-cell Lymphoma (DLBCL): A Post-hoc Analysis of the SADAL Study
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Schuster, M. Zijlstra, J. Casasnovas, R.-O. Vermaat, J.S.P. Kalakonda, N. Goy, A. Choquet, S. Neste, E.V.D. Hill, B. Thieblemont, C. Cavallo, F. De la Cruz, F. Kuruvilla, J. Hamad, N. Jaeger, U. Caimi, P. Gurion, R. Warzocha, K. Bakhshi, S. Sancho, J.-M. Follows, G. Egyed, M. Offner, F. Vassilakopoulos, T. Samal, P. Ku, M. Ma, X. Corona, K. Chamoun, K. Shah, J. Shacham, S. Kauffman, M.G. Canales, M. Maerevoet, M.
- Abstract
Background: Despite a number of treatment options, patients with diffuse large B-cell lymphoma (DLBCL) whose disease has become refractory to treatment have a poor prognosis. Selinexor is a novel, oral drug that is approved to treat patients with relapsed/refractory DLBCL. In this post hoc analysis of the SADAL study, a multinational, open-label study, we evaluated subpopulations to determine if response to single agent selinexor is impacted by number of lines of prior treatment, autologous stem cell transplant (ASCT), response to first and most recent therapies, and time to progressive disease. Patients: Patients (n = 134) with DLBCL after 2-5 prior therapies were enrolled in SADAL and received 60mg selinexor twice weekly. Results: The median overall survival was 9.0 months and median progression free survival was 2.6 months. Patients who had the best overall response rate (ORR) and disease control rate were those who had prior ASCT (42.5% and 50.0%) or responded to last line of therapy (35.9% and 43.5%). Patients with primary refractory DLBCL also showed responses (ORR 21.8%). Adverse events between subgroups were similar to the overall study population, the most common being thrombocytopenia (29.1%), fatigue (7.5%), and nausea (6.0%). Conclusion: Regardless of prior therapy and disease refractory status, selinexor treatment demonstrated results consistent with its novel mechanism of action and lack of cross-resistance. Thus, single agent oral selinexor can induce deep, durable, and tolerable responses in patients with DLBCL who have recurrent disease after several chemoimmunotherapy combination regimens. © 2021
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- 2022
3. Five‐year efficacy and safety of tafasitamab in patients with relapsed or refractory DLBCL: Final results from the Phase II L‐MIND study.
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Duell, J., Abrisqueta, P., Andre, M., Augustin, M., Gaidano, G., Barca, E. G., Jurczak, W., Kalakonda, N., Liberati, A. M., Maddocks, K. J., Menne, T., Nagy, Z., Tournilhac, O., Bakuli, A., Amin, A., Gurbanov, K., and Salles, G.
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DIFFUSE large B-cell lymphomas ,PATIENT safety ,ANTIBODY-dependent cell cytotoxicity ,CURATIVE medicine - Abstract
Encore Abstract - previously submitted to AACR 2023 The research was funded by: MorphoSys AG Keyword: Aggressive B-cell non-Hodgkin lymphoma B Conflicts of interests pertinent to the abstract. b B J. Duell b Research funding: MorphoSys AG, Regeneron B P. Abrisqueta b Consultant or advisory role: Janssen, Celgene, AbbVie, AstraZeneca Honoraria: Janssen, Celgene, AbbVie, AstraZeneca, Gilead Other remuneration: Speakers' bureau: Janssen, Celgene, AbbVie, AstraZeneca, Gilead B M. Andre b Research funding: Roche, Johnson & Johnson, Takeda Educational grants: Roche, Bristol-Myers-Squib, Celgene, Gilead, AbbVie, AstraZeneca Other remuneration: Advisory board: Takeda, Bristol-Myers-Squibb, Karyopharm, Gilead, Incyte. B Introduction: b Tafasitamab, an anti-CD19 immunotherapy that enhances antibody-dependent cellular cytotoxicity and phagocytosis, received accelerated approval in the USA and conditional authorization in Europe in combination with lenalidomide (LEN) for patients (pts) with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem cell transplant (ASCT) based on the results of the open-label, multicenter, single-arm, Phase II L-MIND study (NCT02399085; Salles G., et al. [Extracted from the article]
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- 2023
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4. Health-related quality of life and utility outcomes with selinexor in relapsed/refractory diffuse large B-cell lymphoma
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Shah, J., Shacham, S., Kauffman, M., Daniele, P., Tomaras, D., Tremblay, G., Casasnovas, R.O., Maerevoet, M., Zijlstra, J., Follows, G., Vermaat, J.S.P., Kalakonda, N., Goy, A.H., Choquet, S., Neste, E. van den, Hill, B.T., Thieblemont, C., Cavallo, F., Cruz, F. de la, Kuruvilla, J., Hamad, N., Bouabdallah, R., Jager, U., Caimi, P., Gurion, R., Warzocha, K., Bakhshi, S., Sancho, J.M., Schuster, M., Egyed, M., Offner, F., Vasilakopoulos, T.P., Samal, P., Nagy, A., Ku, M., and Albendea, M.A.C.
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health-related quality of life ,disutility of adverse events ,EQ-5D-5L ,diffuse large B-cell lymphoma ,health utility ,FACT-Lym ,patient reported outcomes ,health state utility ,selinexor - Abstract
Aim: Evaluate health-related quality of life (HRQoL) and health utility impact of single-agent selinexor in heavily pretreated patients with relapsed/refractory diffuse large B-cell lymphoma. Patients & methods: Functional Assessment of Cancer Therapy (FACT) - Lymphoma and EuroQoL five-dimensions five-levels data collected in the single-arm Phase IIb trial SADAL (NCT02227251) were analyzed with mixed-effects models. Results: Treatment responders maintained higher FACT - Lymphoma (p = 3 adverse events and serious adverse events were not associated with clinically meaningful negative QoL impacts.
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- 2021
5. Health-related quality of life and utility outcomes with selinexor in relapsed/refractory diffuse large B-cell lymphoma
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Shah, J. Shacham, S. Kauffman, M. Daniele, P. Tomaras, D. Tremblay, G. Casasnovas, R.-O. Maerevoet, M. Zijlstra, J. Follows, G. P Vermaat, J.S. Kalakonda, N. Goy, A.H. Choquet, S. Den Neste, E.V. Hill, B.T. Thieblemont, C. Cavallo, F. La Cruz, F.D. Kuruvilla, J. Hamad, N. Bouabdallah, R. Jäger, U. Caimi, P. Gurion, R. Warzocha, K. Bakhshi, S. Sancho, J.M. Schuster, M. Egyed, M. Offner, F. Vasilakopoulos, T.P. Samal, P. Nagy, A. Ku, M. Canales Albendea, M.Á.
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Aim: Evaluate health-related quality of life (HRQoL) and health utility impact of single-agent selinexor in heavily pretreated patients with relapsed/refractory diffuse large B-cell lymphoma. Patients & methods: Functional Assessment of Cancer Therapy (FACT)-Lymphoma and EuroQoL five-dimensions five-levels data collected in the single-arm Phase IIb trial SADAL (NCT02227251) were analyzed with mixed-effects models. Results: Treatment responders maintained higher FACT-Lymphoma (p ≤ 0.05), FACT-General (p < 0.05) and EuroQoL five-dimensions five-levels index scores (p < 0.001) beginning in cycle 3. The estimated difference in health state utilities for treatment response and progressive disease was both statistically significant and clinically meaningful (mean difference: 0.07; p = 0.001). Conclusion: In patients with relapsed/refractory diffuse large B-cell lymphoma, objective response to selinexor was associated with HRQoL maintenance, reduction in disease-related HRQoL decrements and higher health utilities. © 2021 Patrick Daniele.
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- 2021
6. Histone H4 lysine 20 monomethylation promotes transcriptional repression by L3MBTL1
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Kalakonda, N, Fischle, W, Boccuni, P, Gurvich, N, Hoya-Arias, R, Zhao, X, Miyata, Y, MacGrogan, D, Zhang, J, Sims, J K, Rice, J C, and Nimer, S D
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- 2008
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7. Selinexor in patients with relapsed or refractory diffuse large B -cell lymphoma (SADAL): a single -arm, multinational, multicentre, open -label, phase 2 trial
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Kalakonda, N., Maerevoet, M., Cavallo, F., Follows, G., Goy, A., Vermaat, J.S.P., Casasnovas, O., Hamad, N., Zijlstra, J.M., Bakhshi, S., Bouabdallah, R., Choquet, S., Gurion, R., Hill, B., Jaeger, U., Sancho, J.M., Schuster, M., Thieblemont, C., Cruz, F. de la, Egyed, M., Mishra, S., Offner, F., Vassilakopoulos, T.P., Warzocha, K., McCarthy, D., Ma, X.W., Corona, K., Saint-Martin, J.R., Chang, H., Landesman, Y., Joshi, A., Wang, H.W., Shah, J., Shacham, S., Kauffman, M., Neste, E. van den, and Canales, M.A.
- Abstract
Background Relapsed or refractory diffuse large B -cell lymphoma (DLBCL) is an aggressive cancer with a median overall survival of less than 6 months. We aimed to assess the response to single -agent selinexor, an oral selective inhibitor of nuclear export, in patients with relapsed or refractory DLBCL who had no therapeutic options of potential clinical benefit. Methods SADAL was a multicentre, multinational, open -label, phase 2b study done in 59 sites in 19 countries. Patients aged 18 years or older with pathologically confirmed diffuse large B -cell lymphoma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received two to five lines of previous therapies, and progressed after or were not candidates for autologous stem -cell transplantation were enrolled. Germinal centre B -cell or non -germinal centre B -cell tumour subtype and double or triple expressor status were determined by immunohistochemistry and double or triple hit status was determined by cytogenetics. Patients received 60 mg selinexor orally on days 1 and 3 weekly until disease progression or unacceptable toxicity. The study was initially designed to evaluate both 60 mg and 100 mg twice -weekly doses of selinexor; however, the 100 mg dose was discontinued in the protocol (version 7.0) on March 29, 2017, when an improved therapeutic window was observed at 60 mg. Primary outcome was overall response rate. The primary outcome and safety were assessed in all patients who received 60 mg selinexor under protocol version 6.0, or enrolled under protocol versions 7.0 or higher and received at least one dose of selinexor. This trial is registered at ClinicalTrials.gov, NCT02227251 (active but not enrolling). Findings Between Oct 21, 2015, and Nov 2, 2019, 267 patients were randomly assigned, with 175 allocated to the 60 mg group and 92 to the discontinued 100 mg group. 48 patients assigned to the 60 mg group were excluded due to enrolment before version 6.0 of the protocol; the remaining 127 patients received selinexor 60 mg and were included in analyses of primary outcome and safety. The overall response rate was 28% (36/127; 95% CI 20?7-37?0); 15 (12%) achieved a complete response and 21 (17%) a partial response. The most common grade 3-4 adverse events were thrombocytopenia (n=58), neutropenia (n=31), anaemia (n=28), fatigue (n=14), hyponatraemia (n=10), and nausea (n=8). The most common serious adverse events were pyrexia (n=9), pneumonia (n=6), and sepsis (n=6). There were no deaths judged as related to treatment with selinexor. Interpretation Single -drug oral selinexor induced durable responses and had a manageable adverse events profile in patients with relapsed or refractory DLBCL who received at least two lines of previous chemoimmunotherapy. Selinexor could be considered a new oral, non-cytotoxic treatment option in this setting.
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- 2020
8. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial
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Kalakonda, N. Maerevoet, M. Cavallo, F. Follows, G. Goy, A. Vermaat, J.S.P. Casasnovas, O. Hamad, N. Zijlstra, J.M. Bakhshi, S. Bouabdallah, R. Choquet, S. Gurion, R. Hill, B. Jaeger, U. Sancho, J.M. Schuster, M. Thieblemont, C. De la Cruz, F. Egyed, M. Mishra, S. Offner, F. Vassilakopoulos, T.P. Warzocha, K. McCarthy, D. Ma, X. Corona, K. Saint-Martin, J.-R. Chang, H. Landesman, Y. Joshi, A. Wang, H. Shah, J. Shacham, S. Kauffman, M. Van Den Neste, E. Canales, M.A.
- Abstract
Background: Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer with a median overall survival of less than 6 months. We aimed to assess the response to single-agent selinexor, an oral selective inhibitor of nuclear export, in patients with relapsed or refractory DLBCL who had no therapeutic options of potential clinical benefit. Methods: SADAL was a multicentre, multinational, open-label, phase 2b study done in 59 sites in 19 countries. Patients aged 18 years or older with pathologically confirmed diffuse large B-cell lymphoma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received two to five lines of previous therapies, and progressed after or were not candidates for autologous stem-cell transplantation were enrolled. Germinal centre B-cell or non-germinal centre B-cell tumour subtype and double or triple expressor status were determined by immunohistochemistry and double or triple hit status was determined by cytogenetics. Patients received 60 mg selinexor orally on days 1 and 3 weekly until disease progression or unacceptable toxicity. The study was initially designed to evaluate both 60 mg and 100 mg twice-weekly doses of selinexor; however, the 100 mg dose was discontinued in the protocol (version 7.0) on March 29, 2017, when an improved therapeutic window was observed at 60 mg. Primary outcome was overall response rate. The primary outcome and safety were assessed in all patients who received 60 mg selinexor under protocol version 6.0, or enrolled under protocol versions 7.0 or higher and received at least one dose of selinexor. This trial is registered at ClinicalTrials.gov, NCT02227251 (active but not enrolling). Findings: Between Oct 21, 2015, and Nov 2, 2019, 267 patients were randomly assigned, with 175 allocated to the 60 mg group and 92 to the discontinued 100 mg group. 48 patients assigned to the 60 mg group were excluded due to enrolment before version 6.0 of the protocol; the remaining 127 patients received selinexor 60 mg and were included in analyses of primary outcome and safety. The overall response rate was 28% (36/127; 95% CI 20·7–37·0); 15 (12%) achieved a complete response and 21 (17%) a partial response. The most common grade 3–4 adverse events were thrombocytopenia (n=58), neutropenia (n=31), anaemia (n=28), fatigue (n=14), hyponatraemia (n=10), and nausea (n=8). The most common serious adverse events were pyrexia (n=9), pneumonia (n=6), and sepsis (n=6). There were no deaths judged as related to treatment with selinexor. Interpretation: Single-drug oral selinexor induced durable responses and had a manageable adverse events profile in patients with relapsed or refractory DLBCL who received at least two lines of previous chemoimmunotherapy. Selinexor could be considered a new oral, non-cytotoxic treatment option in this setting. Funding: Karyopharm Therapeutics Inc. © 2020 Elsevier Ltd
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- 2020
9. Kinobead profiling reveals reprogramming of B-cell receptor signaling in response to therapy within primary CLL cells
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Linley, AJ, Griffin, R, Cicconi, S, D’Avola, A, MacEwan, DJ, Pettit, AR, Kalakonda, N, Packham, G, Prior, IA, and Slupsky, JR
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Induction of signaling via cell surface receptor activation is a critical driver of CLL pathobiology, especially via the B-cell receptor (BCR), which promotes tumor survival and progression. The vital nature of BCR signaling has been recognized through the development of kinase inhibitors (KI), most notably ibrutinib, that target key nodes within this pathway. Current efforts to monitor signaling investigate expression of a highly confined series of kinases and phosphoproteins. While generating key insights, full appreciation of their wider significance to malignant pathology and therapy response remains an unresolved issue. Here, we describe a kinobead-based protocol, used in conjunction with mass-spectrometry (MS) or immunoblotting, to study surface-IgM (sIgM) signaling within primary CLL cells. Employing this approach, we isolated a ‘fingerprint’ of over 30 kinases which displayed unique, patient-specific response to sIgM stimulation, and which displayed greater activation change in CLL cells from patients who had undergone prior chemoimmunotherapy (CIT) compared to those from untreated/treatment-naïve patients. Matched sample analysis of ARCTIC/AdMIRe clinical trial patients revealed the unique nature of the kinome response was present at the intra-patient level, while longitudinal profiling of IcICLLe trial patients supported this as well as showing our finding related to ibrutinib therapy. Refinement of the kinome fingerprint determined 4 kinases linked to proliferation found to be present to a significantly higher level within previously treated patient cells. Proliferation assays confirmed that these patients possess higher proliferative capacity, implying alterations of signaling resulting in promoting of biological processes critical to malignant cells. Collectively, these data represent the first comprehensive investigation into BCR signaling response within CLL, where our probing of kinase active sites reveals unique evidence of adaptive reprogramming in response to therapy. Key points sIgM signaling patterns alter following in vivo therapy using either chemoimmunotherapy or ibrutinib. Kinobeads provide a novel method for high-resolution investigation of signaling in primary CLL cells.
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- 2019
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10. Hematopoietic stem cell mobilization with intravenous melphalan and G-CSF in patients with chemoresponsive multiple myeloma: report of a phase II trial
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Gupta, S, Zhou, P, Hassoun, H, Kewalramani, T, Reich, L, Costello, S, Drake, L, Klimek, V, Dhodapkar, M, Teruya-Feldstein, J, Hedvat, C, Kalakonda, N, Fleisher, M, Filippa, D, Qin, J, Nimer, S D, and Comenzo, R L
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- 2005
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11. SAFETY AND EFFICACY OF THE PD‐L1 INHIBITOR DURVALUMAB WITH R‐CHOP OR R2‐CHOP IN SUBJECTS WITH PREVIOUSLY UNTREATED, HIGH‐RISK DLBCL
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Nowakowski, Grzegorz S., Willenbacher, Wolfgang, Greil , R., Larsen, Thomas Stauffer, Patel, K., Jäger, U., Manges, R.F., Trumper, Lorenz, Haioun, C., Everaus, H, Kalakonda, N., Knoble, J., Brown, Peter de Nully, Jørgensen, J.M., Cunningham, D., Domper Rubio, N., Casadebaig, M., Manzke, O., and Munoz, J.
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- 2019
12. Systemic AL amyloidosis due to non-Hodgkinʼs lymphoma: an unusual clinicopathologic association
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Cohen, A. D., Zhou, P., Xiao, Q., Fleisher, M., Kalakonda, N., Akhurst, T., Chitale, D. A., Moscowitz, C., Dhodapkar, M. V., Teruya-Feldstein, J., Filippa, D., and Comenzo, R. L.
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- 2004
13. CHOP versus GEM-P in previously untreated patients with peripheral T-cell lymphoma (CHEMO-T): a phase 2, multicentre, randomised, open-label trial
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Gleeson, M., Peckitt, C., To, Y.M., Edwards, L., Oates, J., Wotherspoon, A., Attygalle, A.D., Zerizer, I., Sharma, B., Chua, S., Begum, R., Chau, I., Johnson, P., Ardeshna, K.M., Hawkes, E.A., Macheta, M.P., Collins, G.P., Radford, J., Forbes, A., Hart, A., Montoto, S., McKay, P., Benstead, K., Morley, N., Kalakonda, N., Hasan, Y., Turner, D., and Cunningham, D.
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Aged, 80 and over ,Male ,Manchester Cancer Research Centre ,ResearchInstitutes_Networks_Beacons/mcrc ,Lymphoma, T-Cell, Peripheral ,Middle Aged ,Deoxycytidine ,Methylprednisolone ,Gemcitabine ,Article ,Doxorubicin ,Vincristine ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Prednisone ,Female ,Cisplatin ,Cyclophosphamide ,Aged - Abstract
Background: Outcomes with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) or CHOP-like chemotherapy in peripheral T-cell lymphoma are poor. We investigated whether the regimen of gemcitabine, cisplatin, and methylprednisolone (GEM-P) was superior to CHOP as front-line therapy in previously untreated patients. Methods: We did a phase 2, parallel-group, multicentre, open-label randomised trial in 47 hospitals: 46 in the UK and one in Australia. Participants were patients aged 18 years and older with bulky (tumour mass diameter >10 cm) stage I to stage IV disease (WHO performance status 0–3), previously untreated peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T-cell lymphoma, anaplastic lymphoma kinase-negative anaplastic large cell lymphoma, enteropathy-associated T-cell lymphoma, or hepatosplenic γδ T-cell lymphoma. We randomly assigned patients (1:1) stratified by subtype of peripheral T-cell lymphoma and international prognostic index to either CHOP (intravenous cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [maximum 2 mg] on day 1, and oral prednisolone 100 mg on days 1–5) every 21 days for six cycles; or GEM-P (intravenous gemcitabine 1000 mg/m2 on days 1, 8, and 15, cisplatin 100 mg/m2 on day 15, and oral or intravenous methylprednisolone 1000 mg on days 1–5) every 28 days for four cycles. The primary endpoint was the proportion of patients with a CT-based complete response or unconfirmed complete response on completion of study chemotherapy, to detect a 20% superiority of GEM-P compared with CHOP, assessed in all patients who received at least one cycle of treatment and had an end-of-treatment CT scan or reported clinical progression as the reason for stopping trial treatment. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov (NCT01719835) and the European Clinical Trials Database (EudraCT 2011-004146-18). Findings: Between June 18, 2012, and Nov 16, 2016, we randomly assigned 87 patients to treatment, 43 to CHOP and 44 to GEM-P. A planned unmasked review of efficacy data by the independent data monitoring committee in November, 2016, showed that the number of patients with a confirmed or unconfirmed complete response with GEM-P was non-significantly inferior compared with CHOP and the trial was closed early. At a median follow-up of 27·4 months (IQR 16·6–38·4), 23 patients (62%) of 37 assessable patients assigned to CHOP had achieved a complete response or unconfirmed complete response compared with 17 (46%) of 37 assigned to GEM-P (odds ratio 0·52, 95% CI 0·21–1·31; p=0·164). The most common adverse events of grade 3 or worse in both groups were neutropenia (17 [40%] with CHOP and nine [20%] with GEM-P), thrombocytopenia (4 [10%] with CHOP and 13 [30%] with GEM-P, and febrile neutropenia (12 [29%] with CHOP and 3 [7%] with GEM-P). Two patients (5%) died during the study, both in the GEM-P group, from lung infections. Interpretation: The number of patients with a complete response or unconfirmed complete response did not differ between the groups, indicating that GEM-P was not superior for this outcome. CHOP should therefore remain the reference regimen for previously untreated peripheral T-cell lymphoma. Funding: Bloodwise and the UK National Institute of Health Research.
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- 2018
14. PCN325 Health Utility in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (RR-DLBCL) Patients - Results of a Phase II Trial with ORAL Selinexor
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Casasnovas, R.O., Daniele, P., Tremblay, G., Maerevoet, M., Zijlstra, J., Follows, G., Vermaat, J.S.P., Kalakonda, N., Goy, A.H., Choquet, S., Van Den Neste, E., Hill, B.T., Thieblemont, C., Cavallo, F., de la Cruz, F., Kuruvilla, J., Hamad, N., Bouabdallah, R., Jäger, U., Caimi, P., Gurion, R., Warzocha, K., Bakhshi, S., Sancho, J.M., Schuster, M., Egyed, M., Offner, F., Vasilakopoulos, T., Samal, P., Nagy, A., Ku, M., and Canales Albendea, M.Á.
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- 2020
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15. CREATION OF ISOGENIC CELL LINE MODELS OF 17P DELETION TO STUDY CLONAL EVOLUTION AND MECHANISMS OF THERAPY RESISTANCE IN CLL AND DLBCL.
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van Kampen, F. L., Glenn, M., Pettitt, A., Kalakonda, N., and Slupsky, J.
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CELL lines ,CHRONIC lymphocytic leukemia ,DIFFUSE large B-cell lymphomas ,B cell lymphoma ,CD19 antigen - Abstract
B Introduction: b A deletion of chromosome 17p (del17p), on which the tumour suppressor gene I TP53 i is located, is a prevalent genetic aberration in many cancer types. B Results: b Isogenic HCT116 cell lines with hemizygous and homozygous I TP53 i deletion, as well as hemizygous 17p deletion were obtained (Figure 1). [Extracted from the article]
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- 2023
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16. FINAL RESULTS OF THE NCRI CLL210 TRIAL OF ALEMTUZUMAB, DEXAMETHASONE AND LENALIDOMIDE IN PATIENTS WITH HIGH-RISK CLL (ORIGINAL PROTOCOL)
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Pettitt, A. R., Polydoros, F., Dodd, J., Oates, M., Lin, K., Kalakonda, N., Mccarthy, H., Bloor, A., Schuh, A., Duncombe, A., Dearden, C., Fegan, C., Kennedy, B., Christina Yap, Coupland, S. E., and Hillmen, P.
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- 2016
17. SAFETY AND EFFICACY OF THE PD‐L1 INHIBITOR DURVALUMAB WITH R‐CHOP OR R2‐CHOP IN SUBJECTS WITH PREVIOUSLY UNTREATED, HIGH‐RISK DLBCL.
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Nowakowski, G., Willenbacher, W., Greil, R., Larsen, T.S., Patel, K., Jäger, U., Manges, R.F., Trümper, L., Haioun, C., Everaus, H., Kalakonda, N., Knoble, J., Nully Brown, P., Jørgensen, J.M., Cunningham, D., Domper Rubio, N., Casadebaig, M., Manzke, O., and Munoz, J.
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STOCK ownership - Published
- 2019
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18. A PHASE 2B STUDY OF SELINEXOR IN PATIENTS WITH RELAPSED/REFRACTORY (R/R) DIFFUSE LARGE B‐CELL LYMPHOMA (DLBCL).
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Kalakonda, N., Cavallo, F., Follows, G., Goy, A., Vermaat, J., Casasnovas, O., Lavee, O., Maerevoet, M., Zijlstra, J., Bakshi, S., Bouabdallah, R., Choquet, S., Gurion, R., Hill, B., Jaeger, U., Sancho, J., Schuster, M., Thieblemont, C., De la Cruz, F., and Egyed, M.
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DIFFUSE large B-cell lymphomas ,LYMPHOMAS ,TUMOR suppressor proteins - Published
- 2019
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19. research paper Systemic AL amyloidosis due to non-Hodgkin's lymphoma: an unusual clinicopathologic association.
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Cohen, A.D., Zhou, P., Xiao, Q., Fleisher, M., kalakonda, N., Akhurst, T., Chitale, D.A., Moscowitz, C., Dhodapkar, M.V., Teruya-Feldstein, J., Filippa, D., and Comenzo, R.L.
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AMYLOIDOSIS ,LYMPHOMAS ,PLASMA cells ,PROTEIN metabolism disorders ,IMMUNOGLOBULINS ,RITUXIMAB - Abstract
Systemic AL amyloidosis (AL) is a disorder in which light chains form fibrillar deposits, leading to organ dysfunction and death. Rarely, AL has been associated with non-Hodgkin's lymphoma (NHL), although this association has not been well characterized. We report a series of six patients with AL associated with NHL, primarily lymphoplasmacytic lymphoma. Organ involvement was variable, with frequent bulky lymphadenopathy and visceral cavity deposits, but no cardiac involvement. Positron emission tomography scans were negative. Bone marrow and lymph node biopsies showed a mixed population of CD20
+ lymphoid and CD138+ plasma cells. Serum free light chains were elevated, and correlated with response to therapy. Immunoglobulin light chain variable region (Ig VL ) germline gene use was typical for AL, reflecting previously observed correlations between germline gene use and organ tropism. Five patients received rituximab-based therapies with two responses. Two patients underwent autologous stem cell transplantation with one complete haematological response. Four patients survive at 10–132 months from diagnosis. AL with NHL has distinctive clinical features but employs the same Ig VL gene repertoire as AL with clonal plasma cell dyscrasias. Serial serum free light chain levels are useful for tracking response to therapy. Treatments aimed at both lymphoid and plasma cell components appear warranted. [ABSTRACT FROM AUTHOR]- Published
- 2004
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20. EXPLORATORY BIOMARKER ANALYSIS IN THE PH 3 ECHELON‐1 STUDY: WORSE OUTCOME WITH ABVD IN PATIENTS WITH ELEVATED BASELINE LEVELS OF SCD30 AND TARC.
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Radford, J., Connors, J.M., Younes, A., Gallamini, A., Ansell, S.M., Kim, W.S., Cheong, J., Flinn, I., Kalakonda, N., Kaminski, M., Pettengell, R., Onsum, M., Josephson, N., Kuroda, S., Liu, R., Miao, H., Gautam, A., Trepicchio, W.L., and Sureda, A.
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ANTIBODY-drug conjugates ,STOCK ownership - Published
- 2019
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21. NCRI PETREA TRIAL: A PHASE 3 EVALUATION OF PET‐GUIDED, RESPONSE‐ADAPTED THERAPY IN PATIENTS WITH PREVIOUSLY UNTREATED, ADVANCED‐STAGE, HIGH‐TUMOUR‐BURDEN FOLLICULAR LYMPHOMA.
- Author
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Pettitt, A.R., Barrington, S., Kalakonda, N., Khan, U.T., Jackson, R., Carruthers, S., Oates, M., Lin, K., Ardeshna, K., Eyre, T., Fox, C.P., Kennedy, B., Linton, K., Malladi, R., Menne, T., Okosun, J., Paneesha, S., Rule, S., Johnston, A., and Trotman, J.
- Subjects
POSITRON emission tomography - Published
- 2019
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22. BRIEF CO‐ADMINISTRATION OF IDELALISIB MAY IMPROVE THE LONG‐TERM EFFICACY OF FRONTLINE CHEMOIMMUNOTHERAPY IN CHRONIC LYMPHOCYTIC LEUKAEMIA: 3‐YEAR FOLLOW‐UP FROM THE RIALTO TRIAL.
- Author
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Pettitt, A., Kalakonda, N., Cicconi, S., Murphy, C., Menon, G., Coupland, S.E., Oates, M., Lin, K., Pocock, C., Jenkins, S., Schuh, A., Wandroo, F., Rassam, S., Duncombe, A.S., Cervi, P., Paneesha, S., Aldouri, M., Fox, C., Knechtli, C., and Hamblin, M.
- Subjects
FLUDARABINE ,FOLLOW-up studies (Medicine) ,CHRONIC lymphocytic leukemia - Published
- 2019
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- View/download PDF
23. POTENTIAL THERAPEUTIC ADVANTAGE FOR DUVELISIB IN MANTLE CELL LYMPHOMA: PI3Kδ AND OVEREXPRESSED PI3Kγ IN LYMPHOMA CELLS HAVE SPECIALIZED FUNCTIONAL ROLES.
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Till, K.J., Gallardo Zapata, J., Marks, T., Weaver, D.T., Pachter, J.A., Abdullah, M., Kalakonda, N., Pettitt, A.R., and Slupsky, J.R.
- Subjects
MANTLE cell lymphoma ,CELLS - Published
- 2019
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- View/download PDF
24. PRIMARY ANALYSIS RESULTS OF THE SINGLE‐ARM PHASE II STUDY OF MOR208 PLUS LENALIDOMIDE IN PATIENTS WITH RELAPSED OR REFRACTORY DIFFUSE LARGE B‐CELL LYMPHOMA (L‐MIND).
- Author
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Salles, G., Duell, J., González Barca, E., Jurczak, W., Liberati, A.M., Nagy, Z., Obr, A., Gaidano, G., Andre, M., Kalakonda, N., Dreyling, M., Zinzani, P.L., Dirnberger‐Hertweck, M., Weirather, J., Ambarkhane, S., and Maddocks, K.
- Subjects
DIFFUSE large B-cell lymphomas ,LYMPHOMAS ,STEM cell transplantation - Published
- 2019
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- View/download PDF
25. EFFECT OF ADDING IDELALISIB TO FRONTLINE OFATUMUMAB PLUS EITHER CHLORAMBUCIL OR BENDAMUSTINE IN LESS FIT PATIENTS WITH CLL: PRELIMINARY RESULTS FROM THE NCRI RIALTO TRIAL.
- Author
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Pettitt, A.R., Kalakonda, N., Polydoros, F., Bickerstaff, M., Menon, G., Coupland, S.E., Oates, M., Lin, K., Pocock, C., Jenkins, S., Schuh, A., Wandroo, F., Rassam, S., Duncombe, A.S., Jenner, M., Cervi, P., Paneesha, S., Aldouri, M., Fox, C.P., and Knechtli, C.
- Published
- 2017
- Full Text
- View/download PDF
26. PHASE II STUDY OF DURVALUMAB (ANTI-PD-L1) COMBINED WITH EITHER R-CHOP OR LENALIDOMIDE AND R-CHOP IN PREVIOUSLY UNTREATED, HIGH-RISK DIFFUSE LARGE B-CELL LYMPHOMA.
- Author
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Jaeger, U., Kalakonda, N., Everaus, H., Fustier, P., Jaeger, J., Manzke, O., and Nowakowski, G.S.
- Published
- 2017
- Full Text
- View/download PDF
27. L-MIND: MOR208 COMBINED WITH LENALIDOMIDE (LEN) IN PATIENTS WITH RELAPSED OR REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA (R-R DLBCL) - A SINGLE-ARM PHASE II STUDY.
- Author
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Salles, G., González Barca, E., Jurczak, W., Liberati, A.M., Duell, J., Nagy, Z., Papajík, T., Andre, M., Kalakonda, N., Dreyling, M., Zinzani, P.L., Ambarkhane, S., Weirather, J., and Maddocks, K.
- Published
- 2017
- Full Text
- View/download PDF
28. Gene expression in arsenic trioxide-resistant multiple myeloma.
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Comenzo, R., Kalakonda, N., and Zhou, P.
- Subjects
- *
GENE expression , *MULTIPLE myeloma , *ARSENIC compounds - Abstract
Focuses on the gene expression in arsenic trioxide-resistant multiple myeloma. Characteristics of multiple myeloma; Significance of gene expression changes displayed by human myeloma cell lines; Activity of arsenic trioxide on malignant cells.
- Published
- 2003
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- View/download PDF
29. Understanding the relevance of epigenetic reprogramming for resistance to HDAC inhibitors in cancer cells
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Perikala, V., Kalakonda, N., and Slupsky, J.
- Subjects
616.99 - Abstract
Therapeutic responses to Histone deacetylase (HDAC) inhibitors (HDACi) in many cancers are well described but development of resistance to HDACi is a major stumbling block. Whether HDACis induce epigenetic reprogramming and how this contributes to relapse is not reported. A CTCL cell line HuT78, and a CLL cell line MEC1, were used to develop HDACi resistant clones (RHuT78 and RMEC1 respectively) that persistently grow in the presence of the clinically used HDAC inhibitor Romidepsin. RHuT78 cells show perturbed trimethylation of histone H3 lysine K4 on Romidepsin treatment which linked to higher protein expression levels of the implicated demethylase KDM5A. Following on from these experiments, a qRT-PCR epigenetic gene expression array was used to quantify levels of 84 epigenetic gene transcripts in RHuT78 cells and significantly altered genes were taken forward for further investigation. Studies of gene expression patterns in parental, resistant and ‘drug holiday’ cell lines of both HuT78 and MEC1 led to particular interest in HDAC8, DNMT3A and DNMT3B. Functional studies showed that HDAC8 overexpression increased proliferation and resistance of HuT78 cells to Romidepsin. Parallel observations suggested an increase in proliferation of resistant cell lines cultured in the presence of the HDACi. This increased proliferation was seen even with lower concentrations of Romidepsin and argues against prolonged monotherapy using HDACis. Significantly, inhibitors of DNA methyltransferases synergised with Romidepsin in a dose and schedule dependent manner, reversing the changes in epigenetic gene expression associated with resistance and causing increased apoptosis in RHuT78 cells. Taken together this thesis identifies and characterises an unacknowledged contribution of epigenetic reprogramming to drug resistance and provides insights into the effects of Romidepsin on the epigenome that could potentially contribute to HDACi resistance.
- Published
- 2016
- Full Text
- View/download PDF
30. UNDERSTANDING THE RELEVANCE OF EPIGENETIC REPROGRAMMING FOR RESISTANCE TO HDAC INHIBITORS IN CANCER CELLS
- Author
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Perikala, V, kalakonda, N, and slupsky, J
- Abstract
Therapeutic responses to Histone deacetylase (HDAC) inhibitors (HDACi) in many cancers are well described but development of resistance to HDACi is a major stumbling block. Whether HDACis induce epigenetic reprogramming and how this contributes to relapse is not reported. A CTCL cell line HuT78, and a CLL cell line MEC1, were used to develop HDACi resistant clones (RHuT78 and RMEC1 respectively) that persistently grow in the presence of the clinically used HDAC inhibitor Romidepsin. RHuT78 cells show perturbed trimethylation of histone H3 lysine K4 on Romidepsin treatment which linked to higher protein expression levels of the implicated demethylase KDM5A. Following on from these experiments, a qRT-PCR epigenetic gene expression array was used to quantify levels of 84 epigenetic gene transcripts in RHuT78 cells and significantly altered genes were taken forward for further investigation. Studies of gene expression patterns in parental, resistant and ‘drug holiday’ cell lines of both HuT78 and MEC1 led to particular interest in HDAC8, DNMT3A and DNMT3B. Functional studies showed that HDAC8 overexpression increased proliferation and resistance of HuT78 cells to Romidepsin. Parallel observations suggested an increase in proliferation of resistant cell lines cultured in the presence of the HDACi. This increased proliferation was seen even with lower concentrations of Romidepsin and argues against prolonged monotherapy using HDACis. Significantly, inhibitors of DNA methyltransferases synergised with Romidepsin in a dose and schedule dependent manner, reversing the changes in epigenetic gene expression associated with resistance and causing increased apoptosis in RHuT78 cells. Taken together this thesis identifies and characterises an unacknowledged contribution of epigenetic reprogramming to drug resistance and provides insights into the effects of Romidepsin on the epigenome that could potentially contribute to HDACi resistance.
31. The management of newly diagnosed large B-cell lymphoma: A British Society for Haematology Guideline.
- Author
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Fox CP, Chaganti S, McIlroy G, Barrington SF, Burton C, Cwynarski K, Eyre TA, Illidge T, Kalakonda N, Kuhnl A, McKay P, and Davies AJ
- Subjects
- Humans, Rituximab, Lymphoma, Large B-Cell, Diffuse diagnosis, Hematology
- Published
- 2024
- Full Text
- View/download PDF
32. Tafasitamab for patients with relapsed or refractory diffuse large B-cell lymphoma: final 5-year efficacy and safety findings in the phase II L-MIND study.
- Author
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Duell J, Abrisqueta P, Andre M, Gaidano G, Gonzales-Barca E, Jurczak W, Kalakonda N, Liberati AM, Maddocks KJ, Menne T, Nagy Z, Tournilhac O, Kuffer C, Bakuli A, Amin A, Gurbanov K, and Salles G
- Subjects
- Humans, Lenalidomide therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Lymphoma, Non-Hodgkin drug therapy, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse pathology
- Abstract
Tafasitamab, an anti-CD19 immunotherapy, is used with lenalidomide for patients with autologous stem cell transplant-ineligible relapsed/refractory diffuse large B-cell lymphoma based on the results of the phase II L-MIND study (NCT02399085). We report the final 5-year analysis of this study. Eighty patients ≥18 years who had received one to three prior systemic therapies, and had Eastern Cooperative Oncology Group performance status 0-2 received up to 12 cycles of co-administered tafasitamab and lenalidomide, followed by tafasitamab monotherapy until disease progression or unacceptable toxicity. The primary endpoint was the best objective response rate. Secondary endpoints included duration of response, progression-free survival, overall survival, and safety. Exploratory analyses evaluated efficacy endpoints by prior lines of therapy. At data cutoff on November 14, 2022, the objective response rate was 57.5%, with a complete response rate of 41.3% (n=33), which was consistent with prior analyses. With a median follow-up of 44.0 months, the median duration of response was not reached. The median progression-free survival was 11.6 months (95% confidence interval [95% CI]: 5.7-45.7) with a median follow-up of 45.6 months. The median overall survival was 33.5 months (95% CI: 18.3-not reached) with a median follow-up of 65.6 months. Patients who had received one prior line of therapy (n=40) showed a higher objective response rate (67.5%; 52.5% complete responses) compared to patients who had received two or more prior lines of therapy (n=40; 47.5%; 30% complete responses), but the median duration of response was not reached in either subgroup. Other exploratory analyses revealed consistent long-term efficacy results across subgroups. Adverse events were consistent with those described in previous reports, were manageable, and their frequency decreased during tafasitamab monotherapy, with no new safety concerns. This final 5-year analysis of L-MIND demonstrates that the immunotherapy combination of tafasitamab and lenalidomide is well tolerated and has long-term clinical benefit with durable responses.
- Published
- 2024
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33. Highly Multiplexed and Simultaneous Characterization of Protein and RNA in Single Cells by Flow or Mass Cytometry Platforms Using Proximity Ligation Assay for RNA.
- Author
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Duckworth AD, Slupsky JR, and Kalakonda N
- Subjects
- In Situ Hybridization, Oligonucleotide Probes, Staining and Labeling, Antibodies, RNA genetics
- Abstract
In situ hybridization of oligonucleotide probes to intracellular RNA allows quantification of predefined gene transcripts within millions of single cells using cytometry platforms. Previous methods have been hindered by the number of RNA that can be analyzed simultaneously. Here we describe a method called proximity ligation assay for RNA (PLAYR) that permits highly multiplexed RNA analysis that can be combined with antibody staining. Potentially any number of RNA combined with antigen can be analyzed together, being limited only by the number of analytes that can be measured simultaneously., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2024
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- View/download PDF
34. 17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.
- Author
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Duell J, Abrisqueta P, Andre M, Augustin M, Gaidano G, Barca EG, Jurczak W, Kalakonda N, Liberati AM, Maddocks KJ, Menne T, Nagy Z, Tournilhac O, Bakuli A, Amin A, Gurbanov K, and Salles G
- Subjects
- Humans, Switzerland, Congresses as Topic, Lymphoma therapy
- Published
- 2023
- Full Text
- View/download PDF
35. PKCβ Facilitates Leukemogenesis in Chronic Lymphocytic Leukaemia by Promoting Constitutive BCR-Mediated Signalling.
- Author
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Hay J, Tarafdar A, Holroyd AK, Moka HA, Dunn KM, Alshayeb A, Lloyd BH, Cassels J, Malik N, Khan AF, Sou I, Lees J, Almuhanna HNB, Kalakonda N, Slupsky JR, and Michie AM
- Abstract
B cell antigen receptor (BCR) signalling competence is critical for the pathogenesis of chronic lymphocytic leukaemia (CLL). Defining key proteins that facilitate these networks aid in the identification of targets for therapeutic exploitation. We previously demonstrated that reduced PKCα function in mouse hematopoietic stem/progenitor cells (HPSCs) resulted in PKCβII upregulation and generation of a poor-prognostic CLL-like disease. Here, prkcb knockdown in HSPCs leads to reduced survival of PKCα-KR-expressing CLL-like cells, concurrent with reduced expression of the leukemic markers CD5 and CD23. SP1 promotes elevated expression of prkcb in PKCα-KR expressing cells enabling leukemogenesis. Global gene analysis revealed an upregulation of genes associated with B cell activation in PKCα-KR expressing cells, coincident with upregulation of PKCβII: supported by activation of key signalling hubs proximal to the BCR and elevated proliferation. Ibrutinib (BTK inhibitor) or enzastaurin (PKCβII inhibitor) treatment of PKCα-KR expressing cells and primary CLL cells showed similar patterns of Akt/mTOR pathway inhibition, supporting the role for PKCβII in maintaining proliferative signals in our CLL mouse model. Ibrutinib or enzastaurin treatment also reduced PKCα-KR-CLL cell migration towards CXCL12. Overall, we demonstrate that PKCβ expression facilitates leukemogenesis and identify that BCR-mediated signalling is a key driver of CLL development in the PKCα-KR model.
- Published
- 2022
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- View/download PDF
36. Effect of Prior Therapy and Disease Refractoriness on the Efficacy and Safety of Oral Selinexor in Patients with Diffuse Large B-cell Lymphoma (DLBCL): A Post-hoc Analysis of the SADAL Study.
- Author
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Schuster M, Zijlstra J, Casasnovas RO, Vermaat JSP, Kalakonda N, Goy A, Choquet S, Neste EVD, Hill B, Thieblemont C, Cavallo F, De la Cruz F, Kuruvilla J, Hamad N, Jaeger U, Caimi P, Gurion R, Warzocha K, Bakhshi S, Sancho JM, Follows G, Egyed M, Offner F, Vassilakopoulos T, Samal P, Ku M, Ma X, Corona K, Chamoun K, Shah J, Shacham S, Kauffman MG, Canales M, and Maerevoet M
- Subjects
- Humans, Hydrazines adverse effects, Triazoles adverse effects, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse pathology, Lymphoma, Non-Hodgkin drug therapy
- Abstract
Background: Despite a number of treatment options, patients with diffuse large B-cell lymphoma (DLBCL) whose disease has become refractory to treatment have a poor prognosis. Selinexor is a novel, oral drug that is approved to treat patients with relapsed/refractory DLBCL. In this post hoc analysis of the SADAL study, a multinational, open-label study, we evaluated subpopulations to determine if response to single agent selinexor is impacted by number of lines of prior treatment, autologous stem cell transplant (ASCT), response to first and most recent therapies, and time to progressive disease., Patients: Patients (n = 134) with DLBCL after 2-5 prior therapies were enrolled in SADAL and received 60mg selinexor twice weekly., Results: The median overall survival was 9.0 months and median progression free survival was 2.6 months. Patients who had the best overall response rate (ORR) and disease control rate were those who had prior ASCT (42.5% and 50.0%) or responded to last line of therapy (35.9% and 43.5%). Patients with primary refractory DLBCL also showed responses (ORR 21.8%). Adverse events between subgroups were similar to the overall study population, the most common being thrombocytopenia (29.1%), fatigue (7.5%), and nausea (6.0%)., Conclusion: Regardless of prior therapy and disease refractory status, selinexor treatment demonstrated results consistent with its novel mechanism of action and lack of cross-resistance. Thus, single agent oral selinexor can induce deep, durable, and tolerable responses in patients with DLBCL who have recurrent disease after several chemoimmunotherapy combination regimens., (Copyright © 2021. Published by Elsevier Inc.)
- Published
- 2022
- Full Text
- View/download PDF
37. COVID-19 outcomes in haematopoietic cell transplant recipients: A systematic review and meta-analysis.
- Author
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Lim YJ, Khan U, Karpha I, Ross A, Saif M, Remberger M, Kalakonda N, Pettitt AR, and Floisand Y
- Abstract
Up-to-date information on coronavirus disease 2019 (COVID-19) outcomes and risk factors in haematopoietic cell transplantation (HCT) recipients is required to inform on decisions about cancer treatment and COVID-19 mitigation strategies. We performed a meta-analysis to address this knowledge gap. All studies with at least five patients who reported COVID-19-related deaths in HCT recipients were included. The primary outcome was COVID-19-related death. Secondary outcomes were COVID-19-related mechanical ventilation (MV) and intensive care unit (ITU) admission. The cumulative COVID-19-related death rate among HCT recipients was 21% (95% confidence interval [CI] 18%-24%), while MV and ITU admission rates were 14% (95% CI 11%-17%) and 18% (95% CI 14%-22%), respectively. Subgroup analysis showed higher death rates in patients who developed COVID-19 within 12 months of HCT (risk ratio [RR] 1.82, 95% CI 1.09-3.03), within 6 months of receiving immunosuppressant drugs (RR 2.11, 95% CI 1.38-3.20) or in the context of active graft-versus-host disease (RR 2.38, 95% CI 1.10-5.16). Our findings support the idea that HCT should remain an integral part of cancer treatment during the COVID-19 pandemic but also highlight the need to prioritise preventative measures in those patients who are at increased risk of adverse COVID-19 outcomes., Competing Interests: Andrew Ross, Indrani Karpha, Muhammad Saif and Yngvar Floisand are employed by Clatterbridge Cancer Centre NHS Foundation Trust. Yeong Jer Lim, Andrew R. Pettitt and Nagesh Kalakonda are employed by the University of Liverpool. Yeong Jer Lim is supported by the NW MRC fellowship scheme (award number MR/N025989/1). Mats Remberger is employed by Uppsala University Hospital, Sweden and supported by grants from the Swedish Research Council (VR 2017‐00355)., (© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2022
- Full Text
- View/download PDF
38. The Association between Patient Characteristics and the Efficacy and Safety of Selinexor in Diffuse Large B-Cell Lymphoma in the SADAL Study.
- Author
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Zijlstra JM, Follows G, Casasnovas RO, Vermaat JSP, Kalakonda N, Choquet S, Hill B, Thieblemont C, Cavallo F, Cruz F, Kuruvilla J, Hamad N, Jaeger U, Caimi P, Gurion R, Warzocha K, Bakhshi S, Sancho JM, Schuster M, Egyed M, Offner F, Vassilakopoulos TP, Samal P, Ku M, Xu J, Corona K, Chamoun K, Shah J, Canales M, and Maerevoet M
- Abstract
Selinexor, an oral selective inhibitor of nuclear export, was evaluated in the Phase 2b SADAL study in patients with diffuse large B-cell lymphoma (DLBCL) who previously received two to five prior systemic regimens. In post hoc analyses, we analyzed several categories of patient characteristics (age, renal function, DLBCL subtype, absolute lymphocyte count, transplant status, number of prior lines of therapy, refractory status, Ann Arbor disease stage, and lactate dehydrogenase) at baseline, i.e., during screening procedures, to determine their potential contributions to the efficacy (overall response rate [ORR], duration of response [DOR], overall survival [OS]) and tolerability of selinexor. Across most categories of characteristics, no significant difference was observed in ORR or DOR. OS was significantly longer for patients < 65 vs. ≥ 65 years, and for those with lymphocyte counts ≥ 1000/µL vs. < 1000/µL or lactate dehydrogenase ≤ ULN vs. > ULN. The most common adverse events (AEs) across the characteristics were thrombocytopenia and nausea, and similar rates of grade 3 AEs and serious AEs were observed. With its oral administration, novel mechanism of action, and consistency in responses in heavily pretreated patients, selinexor may help to address an important unmet clinical need in the treatment of DLBCL.
- Published
- 2022
- Full Text
- View/download PDF
39. Safety and efficacy of durvalumab with R-CHOP or R 2 -CHOP in untreated, high-risk DLBCL: a phase 2, open-label trial.
- Author
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Nowakowski GS, Willenbacher W, Greil R, Larsen TS, Patel K, Jäger U, Manges RF, Trümper L, Everaus H, Kalakonda N, Brown P, Jørgensen JM, Cunningham D, Dell'Aringa J, Fox B, Rubio ND, Kilavuz N, Casadebaig ML, Manzke O, and Munoz J
- Subjects
- Aged, Antibodies, Monoclonal adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cyclophosphamide adverse effects, Cyclophosphamide therapeutic use, Disease-Free Survival, Doxorubicin adverse effects, Doxorubicin therapeutic use, Female, Humans, Male, Middle Aged, Prednisone adverse effects, Prednisone therapeutic use, Rituximab adverse effects, Rituximab therapeutic use, Treatment Outcome, Vincristine adverse effects, Vincristine therapeutic use, Antibodies, Monoclonal therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Lymphoma, Large B-Cell, Diffuse drug therapy
- Abstract
Patients with high-risk diffuse large B-cell lymphoma (DLBCL) have poor outcomes following first-line cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (R-CHOP). Evidence shows chemotherapy and immune checkpoint blockade can increase antitumor efficacy. This study investigated durvalumab, a programmed death-ligand 1 inhibitor, combined with R-CHOP or lenalidomide + R-CHOP (R
2 -CHOP) in newly diagnosed high-risk DLBCL. Patients received durvalumab 1125 mg every 21 days for 2-8 cycles + R-CHOP (non-activated B-cell [ABC] subtype) or R2 -CHOP (ABC), then durvalumab consolidation (1500 mg every 28 days). Of 46 patients, 43 received R-CHOP and three R2 -CHOP. All patients had the high-risk disease; 14 (30.4%) and eight (17.4%) had double- or triple-hit DLBCL, respectively. Following induction, 20/37 (54.1%) patients receiving durvalumab + R-CHOP achieved complete response (CR), and seven (18.9%) partial response (PR); 25 (67.6% [95% CI 50.2-82.0]) continued to consolidation and were progression-free at 12 months. Among efficacy-evaluable patients with double- or triple-hit DLBCL (n = 12), five achieved CR and five PR. Adverse events were generally consistent with R-CHOP. Correlative analyses did not identify conclusive biomarkers of response. Durvalumab + R-CHOP is feasible in DLBCL with no new safety signals, but the combination provided no greater benefit than R-CHOP., (© 2021. Japanese Society of Hematology.)- Published
- 2022
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- View/download PDF
40. Comparison of the Effectiveness and Safety of the Oral Selective Inhibitor of Nuclear Export, Selinexor, in Diffuse Large B Cell Lymphoma Subtypes.
- Author
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Casasnovas RO, Follows G, Zijlstra JM, Vermaat JSP, Kalakonda N, Choquet S, Neste EVD, Hill B, Thieblemont C, Cavallo F, la Cruz F, Kuruvilla J, Hamad N, Jaeger U, Caimi PF, Gurion R, Warzocha K, Bakhshi S, Sancho JM, Schuster M, Egyed M, Offner F, Vassilakopoulos TP, Samal P, Ku M, Ma X, Chamoun K, Shah J, Canales M, Maerevoet M, Shacham S, Kauffman MG, and Goy A
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Hydrazines pharmacology, Lymphoma, Large B-Cell, Diffuse pathology, Male, Middle Aged, Treatment Outcome, Triazoles pharmacology, Hydrazines therapeutic use, Lymphoma, Large B-Cell, Diffuse drug therapy, Triazoles therapeutic use
- Abstract
Background: The SADAL study evaluated oral selinexor in patients with relapsed and/or refractory diffuse large B-cell lymphoma (DLBCL) after at least 2 prior lines of systemic therapy. In this post-hoc analysis, we analyzed the outcomes of the SADAL study by DLBCL subtype to determine the effects of DLBCL subtypes on efficacy and tolerability of selinexor., Patients and Methods: Data from 134 patients in SADAL were analyzed by DLBCL subtypes for overall response rate (ORR), overall survival (OS), duration of treatment response, progression-free survival, and adverse events rate., Results: ORR in the entire cohort was 29.1%, and similar in patients with germinal center (GCB) versus non-GCB DLBCL (31.7% vs. 24.2%, P = 0.45); transformed DLBCL showed a trend towards higher ORR than de novo DLBCL: 38.7% vs. 26.2% (P = 0.23). Despite similar prior treatment regimens and baseline characteristics, patients with DLBCL and normal C-MYC/BCL-2 protein expression levels had a significantly higher ORR (46.2% vs.14.8%, P = 0.012) and significantly longer OS (medians 13.7 vs. 5.1 months, hazard ratio 0.43 [95% CI, 0.23-0.77], P = 0.004) as compared with those whose DLBCL had C-MYC and BCL-2 overexpression. Among patients who had normal expression levels of either C-MYC or BCL-2 and baseline hemoglobin levels ≥ 10g/dL, ORR was 51.5% (n = 47), with median OS of 15.5 months and median PFS of 4.6 months. Similar rates of adverse events were noted in all subgroups., Conclusions: Overall, single agent oral selinexor showed strong responses in patients with limited treatment alternatives regardless of germinal center B-cell type or disease origin., (Copyright © 2021. Published by Elsevier Inc.)
- Published
- 2022
- Full Text
- View/download PDF
41. Role of MYC and BCL2 expression in a cohort of 43 patients with DLBCL: a retrospective study.
- Author
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Khan UT, Kelly M, Dodd J, Fergiani S, Hammer B, Smith J, Arumainathan A, Atherton M, Carter A, Racu-Amoasii I, Kalakonda N, Pettitt A, and Menon G
- Subjects
- Aged, Aged, 80 and over, Biomarkers, Tumor genetics, Disease Progression, Female, Humans, Immunohistochemistry, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse mortality, Male, Middle Aged, Progression-Free Survival, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-myc genetics, Retrospective Studies, Time Factors, Translocation, Genetic, Biomarkers, Tumor analysis, Lymphoma, Large B-Cell, Diffuse chemistry, Proto-Oncogene Proteins c-bcl-2 analysis, Proto-Oncogene Proteins c-myc analysis
- Abstract
Competing Interests: Competing interests: UTK is an MRC Clinical Training Fellow based at the University of Liverpool supported by the North West England Medical Research Council Fellowship Scheme in Clinical Pharmacology and Therapeutics, which is funded by the Medical Research Council (Award Ref. MR/N025989/1), Roche Pharma, Eli Lilly and Company Limited, UCB Pharma, Novartis, the University of Liverpool and the University of Manchester. AP received research funding from Celgene, Chugai, Gilead, GSK/Novartis, Roche and Verastem. NK received research funding from Celgene.
- Published
- 2021
- Full Text
- View/download PDF
42. Kinobead Profiling Reveals Reprogramming of BCR Signaling in Response to Therapy within Primary CLL Cells.
- Author
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Linley AJ, Karydis LI, Mondru AK, D'Avola A, Al Shmrany H, Cicconi S, Griffin R, Forconi F, Pettitt AR, Kalakonda N, Rawstron AC, Hillmen P, Steele AJ, MacEwan DJ, Packham G, Prior IA, and Slupsky JR
- Subjects
- Cytological Techniques methods, Humans, Microspheres, Protein Kinase Inhibitors, Tumor Cells, Cultured, B-Lymphocytes physiology, Leukemia, Lymphocytic, Chronic, B-Cell etiology, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Signal Transduction physiology
- Abstract
Purpose: B-cell receptor (BCR) signaling is critical for the pathogenesis of chronic lymphocytic leukemia (CLL), promoting both malignant cell survival and disease progression. Although vital, understanding of the wider signaling network associated with malignant BCR stimulation is poor. This is relevant with respect to potential changes in response to therapy, particularly involving kinase inhibitors. In the current study, we describe a novel high-resolution approach to investigate BCR signaling in primary CLL cells and track the influence of therapy on signaling response., Experimental Design: A kinobead/mass spectrometry-based protocol was used to study BCR signaling in primary CLL cells. Longitudinal analysis of samples donated by clinical trial patients was used to investigate the impact of chemoimmunotherapy and ibrutinib on signaling following surface IgM engagement. Complementary Nanostring and immunoblotting analysis was used to verify our findings., Results: Our protocol isolated a unique, patient-specific signature of over 30 kinases from BCR-stimulated CLL cells. This signature was associated with 13 distinct Kyoto Encyclopedia of Genes and Genomes pathways and showed significant change in cells from treatment-naïve patients compared with those from patients who had previously undergone therapy. This change was validated by longitudinal analysis of clinical trials samples where BCR-induced kinome responses in CLL cells altered between baseline and disease progression in patients failing chemoimmunotherapy and between baseline and treatment in patients taking ibrutinib., Conclusions: These data comprise the first comprehensive proteomic investigation of the BCR signaling response within CLL cells and reveal unique evidence that these cells undergo adaptive reprogramming of this signaling in response to therapy., (©2021 The Authors; Published by the American Association for Cancer Research.)
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- 2021
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43. Long-term outcomes from the Phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma.
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Duell J, Maddocks KJ, González-Barca E, Jurczak W, Liberati AM, De Vos S, Nagy Z, Obr A, Gaidano G, Abrisqueta P, Kalakonda N, André M, Dreyling M, Menne T, Tournilhac O, Augustin M, Rosenwald A, Dirnberger-Hertweck M, Weirather J, Ambarkhane S, and Salles G
- Subjects
- Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols adverse effects, Humans, Lenalidomide therapeutic use, Transplantation, Autologous, Treatment Outcome, Hematopoietic Stem Cell Transplantation, Lymphoma, Large B-Cell, Diffuse diagnosis, Lymphoma, Large B-Cell, Diffuse drug therapy
- Abstract
Tafasitamab (MOR208), an Fc-modified, humanized, anti-CD19 monoclonal antibody, combined with the immunomodulatory drug lenalidomide was clinically active with a good tolerability profile in the open-label, single-arm, phase II L-MIND study of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem-cell transplantation. To assess long-term outcomes, we report an updated analysis with ≥35 months' follow-up. Patients were aged >18 years, had received one to three prior systemic therapies (including ≥1 CD20-targeting regimen) and Eastern Cooperative Oncology Group performance status 0-2. Patients received 28-day cycles of tafasitamab (12 mg/kg intravenously), once weekly during cycles 1-3, then every 2 weeks during cycles 4-12. Lenalidomide (25 mg orally) was administered on days 1-21 of cycles 1-12. After cycle 12, progression-free patients received tafasitamab every 2 weeks until disease progression. The primary endpoint was best objective response rate. After ≥35 months' follow-up (data cut-off: October 30, 2020), the objective response rate was 57.5% (n=46/80), including a complete response in 40.0% of patients (n=32/80) and a partial response in 17.5% of patients (n=14/80). The median duration of response was 43.9 months (95% confidence interval [95% CI]: 26.1-not reached), the median overall survival was 33.5 months (95% CI: 18.3-not reached) and the median progression-free survival was 11.6 months (95% CI: 6.3-45.7). There were no unexpected toxicities. Subgroup analyses revealed consistent long-term efficacy results across most subgroups of patients. This extended follow-up of L-MIND confirms the long duration of response, meaningful overall survival, and well-defined safety profile of tafasitamab plus lenalidomide followed by tafasitamab monotherapy in patients with relapsed/refractory diffuse large B-cell lymphoma ineligible for autologous stem cell transplantation. ClinicalTrials.gov identifier: NCT02399085.
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- 2021
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44. Survival among patients with relapsed/refractory diffuse large B cell lymphoma treated with single-agent selinexor in the SADAL study.
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Maerevoet M, Zijlstra JM, Follows G, Casasnovas RO, Vermaat JSP, Kalakonda N, Goy A, Choquet S, Van Den Neste E, Hill B, Thieblemont C, Cavallo F, De la Cruz F, Kuruvilla J, Hamad N, Jaeger U, Caimi P, Gurion R, Warzocha K, Bakhshi S, Sancho JM, Schuster M, Egyed M, Offner F, Vassilakopoulos TP, Samal P, Ku M, Ma X, Corona K, Chamoun K, Shah J, Shacham S, Kauffman MG, and Canales M
- Subjects
- Age Factors, Aged, Humans, Lymphoma, Large B-Cell, Diffuse epidemiology, Neoplasm Recurrence, Local epidemiology, Survival Analysis, Treatment Outcome, Hydrazines therapeutic use, Lymphoma, Large B-Cell, Diffuse drug therapy, Neoplasm Recurrence, Local drug therapy, Triazoles therapeutic use
- Abstract
Patients with RR DLBCL who have received ≥ 2 lines of therapy have limited treatment options and an expected overall survival (OS) of < 6 months. The SADAL study evaluated single-agent oral selinexor in patients with RR DLBCL and demonstrated an overall response rate (ORR) of 29.1% with median duration of response (DOR) of 9.3 months. The analyses described here evaluated a number of subpopulations in order to understand how response correlates with survival outcomes in order to identify patients who could most optimally benefit from selinexor treatment. Median age was 67 years; 44.8% of patients were ≥ 70 years of age. The median OS was 9.0 months (95% CI 6.2, 13.7) at a median follow-up of 14.8 months. The median OS was not reached in patients with a CR or PR, while patients who did not respond have a median OS of 4.9 months (p < 0.0001). Patients < 70 years had an OS of 11.1 months compared with 7.8 months in patients ≥ 70 years. Among patients with or without prior ASCT, the median OS was 10.9 and 7.8 months, respectively. Among patients with disease refractory to the most recent DLBCL treatment regimen, the median OS was 7.0 months compared with 11.1 months for disease not refractory to the most recent treatment. In a patient population in which survival is expected to be < 6 months, treatment with single-agent oral selinexor was associated with a median survival of 9 months. Increased median OS observed in patients responding to selinexor was consistent across subgroups regardless of age, prior ASCT therapy, or refractory status. Randomized studies of selinexor in combination with a variety of other anti-DLBCL agents are planned. This trial was registered at ClinicalTrials.gov (NCT02227251) on August 28, 2014. https://clinicaltrials.gov/ct2/show/NCT02227251 ., (© 2021. The Author(s).)
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- 2021
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45. Haematological malignancy and nosocomial transmission are associated with an increased risk of death from COVID-19: results of a multi-center UK cohort.
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Bhogal T, Khan UT, Lee R, Stockdale A, Hesford C, Potti-Dhananjaya V, Jathanna A, Rahman S, Tivey A, Shotton R, Sundar R, Valerio C, Norouzi A, Walker P, Suckling R, Armstrong A, Brearton G, Pettitt A, Kalakonda N, Palmer DH, Jackson R, Turtle L, and Palmieri C
- Subjects
- COVID-19 Testing, Female, Humans, Pandemics, Retrospective Studies, Risk Factors, SARS-CoV-2, United Kingdom epidemiology, COVID-19, Cross Infection epidemiology, Hematologic Neoplasms epidemiology
- Abstract
The COVID-19 pandemic has been a disruptive event for cancer patients, especially those with haematological malignancies (HM). They may experience a more severe clinical course due to impaired immune responses. This multi-center retrospective UK audit identified cancer patients who had SARS-CoV-2 infection between 1 March and 10 June 2020 and collected data pertaining to cancer history, COVID-19 presentation and outcomes. In total, 179 patients were identified with a median age of 72 (IQR 61, 81) and follow-up of 44 days (IQR 42, 45). Forty-one percent were female and the overall mortality was 37%. Twenty-nine percent had HM and of these, those treated with chemotherapy in the preceding 28 days to COVID-19 diagnosis had worse outcome compared with solid malignancy (SM): 62% versus 19% died [HR 8.33 (95% CI, 2.56-25), p < 0.001]. Definite or probable nosocomial SARS-CoV-2 transmission accounted for 16% of cases and was associated with increased risk of death (HR 2.47, 95% CI 1.43-4.29, p = 0.001). Patients with haematological malignancies and those who acquire nosocomial transmission are at increased risk of death. Therefore, there is an urgent need to reassess shielding advice, reinforce stringent infection control, and ensure regular patient and staff testing to prevent nosocomial transmission.
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- 2021
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46. Health-related quality of life and utility outcomes with selinexor in relapsed/refractory diffuse large B-cell lymphoma.
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Shah J, Shacham S, Kauffman M, Daniele P, Tomaras D, Tremblay G, Casasnovas RO, Maerevoet M, Zijlstra J, Follows G, P Vermaat JS, Kalakonda N, Goy AH, Choquet S, Den Neste EV, Hill BT, Thieblemont C, Cavallo F, la Cruz F, Kuruvilla J, Hamad N, Bouabdallah R, Jäger U, Caimi P, Gurion R, Warzocha K, Bakhshi S, Sancho JM, Schuster M, Egyed M, Offner F, Vasilakopoulos TP, Samal P, Nagy A, Ku M, and Canales Albendea MÁ
- Subjects
- Adult, Aged, Aged, 80 and over, Drug Resistance, Neoplasm, Female, Humans, Lymphoma, Large B-Cell, Diffuse pathology, Male, Middle Aged, Patient Reported Outcome Measures, Quality of Life, Recurrence, Hydrazines therapeutic use, Lymphoma, Large B-Cell, Diffuse drug therapy, Triazoles therapeutic use
- Abstract
Aim: Evaluate health-related quality of life (HRQoL) and health utility impact of single-agent selinexor in heavily pretreated patients with relapsed/refractory diffuse large B-cell lymphoma. Patients & methods: Functional Assessment of Cancer Therapy (FACT) - Lymphoma and EuroQoL five-dimensions five-levels data collected in the single-arm Phase IIb trial SADAL (NCT02227251) were analyzed with mixed-effects models. Results: Treatment responders maintained higher FACT - Lymphoma (p ≤ 0.05), FACT - General (p < 0.05) and EuroQoL five-dimensions five-levels index scores (p < 0.001) beginning in cycle 3. The estimated difference in health state utilities for treatment response and progressive disease was both statistically significant and clinically meaningful (mean difference: 0.07; p = 0.001). Conclusion: In patients with relapsed/refractory diffuse large B-cell lymphoma, objective response to selinexor was associated with HRQoL maintenance, reduction in disease-related HRQoL decrements and higher health utilities.
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- 2021
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47. Lenalidomide, dexamethasone and alemtuzumab or ofatumumab in high-risk chronic lymphocytic leukaemia: final results of the NCRI CLL210 trial.
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Pettitt AR, Jackson R, Cicconi S, Polydoros F, Yap C, Dodd J, Bickerstaff M, Stackpoole M, Khan UT, Carruthers S, Oates M, Lin K, Coupland SE, Menon G, Kalakonda N, McCarthy H, Bloor A, Schuh A, Duncombe A, Dearden C, Fegan C, Kennedy B, Walewska R, Marshall S, Fox CP, and Hillmen P
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- Alemtuzumab therapeutic use, Antibodies, Monoclonal, Humanized, Dexamethasone therapeutic use, Humans, Lenalidomide therapeutic use, Treatment Outcome, Antineoplastic Agents therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
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- 2020
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48. Selinexor for relapsed or refractory diffuse large B-cell lymphoma: examining the artifact - Authors' reply.
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Kalakonda N, Kauffman M, and Shah J
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- Humans, Hydrazines, Triazoles, Artifacts, Lymphoma, Large B-Cell, Diffuse
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- 2020
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49. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study.
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Salles G, Duell J, González Barca E, Tournilhac O, Jurczak W, Liberati AM, Nagy Z, Obr A, Gaidano G, André M, Kalakonda N, Dreyling M, Weirather J, Dirnberger-Hertweck M, Ambarkhane S, Fingerle-Rowson G, and Maddocks K
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized administration & dosage, Female, Follow-Up Studies, Humans, Lenalidomide administration & dosage, Lymphoma, Large B-Cell, Diffuse pathology, Male, Middle Aged, Neoplasm Recurrence, Local pathology, Prospective Studies, Survival Rate, Treatment Outcome, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Drug Resistance, Neoplasm drug effects, Lymphoma, Large B-Cell, Diffuse drug therapy, Neoplasm Recurrence, Local drug therapy, Salvage Therapy
- Abstract
Background: Patients with relapsed or refractory diffuse large B-cell lymphoma who are ineligible for autologous stem-cell transplantation have poor outcomes and few treatment options. Tafasitamab (MOR208) is an Fc-enhanced, humanised, anti-CD19 monoclonal antibody that has shown preclinical and single-agent activity in patients with relapsed or refractory B-cell malignancies. Preclinical data suggested that tafasitamab might act synergistically with lenalidomide. We aimed to assess the antitumour activity and safety of tafasitamab plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma who were ineligible for autologous stem-cell transplantation., Methods: In this multicentre, open-label, single-arm, phase 2 study (L-MIND), patients older than 18 years with histologically confirmed diffuse large B-cell lymphoma, who relapsed or had refractory disease after previous treatment with one to three systemic regimens (with at least one anti-CD20 therapy), were not candidates for high-dose chemotherapy and subsequent autologous stem-cell transplantation, had an Eastern Cooperative Oncology Group performance status of 0-2, and had measurable disease at baseline were recruited from 35 academic and community hospitals in ten countries. Patients received coadministered intravenous tafasitamab (12 mg/kg) and oral lenalidomide (25 mg/day) for up to 12 cycles (28 days each), followed by tafasitamab monotherapy (in patients with stable disease or better) until disease progression. The primary endpoint was the proportion of patients with an objective response (centrally assessed), defined as a complete or partial response according to the 2007 International Working Group response criteria for malignant lymphoma. Antitumour activity analyses are based on all patients who received at least one dose of both tafasitamab and lenalidomide; safety analyses are based on all patients who received at least one dose of either study medication. Recruitment is complete, and the trial is in follow-up. This trial is registered with ClinicalTrials.gov, NCT02399085., Findings: Between Jan 18, 2016, and Nov 15, 2017, 156 patients were screened: 81 were enrolled and received at least one dose of either study medication, and 80 received at least one dose of both tafasitamab and lenalidomide. Median follow-up was 13·2 months (IQR 7·3-20·4) as of data cutoff on Nov 30, 2018. 48 (60%; 95% CI 48-71) of 80 patients who received tafasitamab plus lenalidomide had an objective response: 34 (43%; 32-54) had a complete response and 14 (18%; 10-28) had a partial response. The most common treatment-emergent adverse events of grade 3 or worse were neutropenia (39 [48%] of 81 patients), thrombocytopenia (14 [17%]), and febrile neutropenia (ten [12%]). Serious adverse events occurred in 41 (51%) of 81 patients. The most frequently reported serious adverse events (in two or more patients) were pneumonia (five [6%]), febrile neutropenia (five [6%]), pulmonary embolism (three [4%]), bronchitis (two [2%]), atrial fibrillation (two [2%]), and congestive cardiac failure (two [2%])., Interpretation: Tafasitamab in combination with lenalidomide was well tolerated and resulted in a high proportion of patients with relapsed or refractory diffuse large B-cell lymphoma ineligible for autologous stem-cell transplantation having a complete response, and might represent a new therapeutic option in this setting., Funding: MorphoSys., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
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- 2020
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50. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial.
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Kalakonda N, Maerevoet M, Cavallo F, Follows G, Goy A, Vermaat JSP, Casasnovas O, Hamad N, Zijlstra JM, Bakhshi S, Bouabdallah R, Choquet S, Gurion R, Hill B, Jaeger U, Sancho JM, Schuster M, Thieblemont C, De la Cruz F, Egyed M, Mishra S, Offner F, Vassilakopoulos TP, Warzocha K, McCarthy D, Ma X, Corona K, Saint-Martin JR, Chang H, Landesman Y, Joshi A, Wang H, Shah J, Shacham S, Kauffman M, Van Den Neste E, and Canales MA
- Subjects
- Adult, Aged, Aged, 80 and over, Disease-Free Survival, Female, Humans, Karyopherins antagonists & inhibitors, Male, Middle Aged, Receptors, Cytoplasmic and Nuclear antagonists & inhibitors, Exportin 1 Protein, Antineoplastic Agents therapeutic use, Hydrazines therapeutic use, Lymphoma, Large B-Cell, Diffuse drug therapy, Triazoles therapeutic use
- Abstract
Background: Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer with a median overall survival of less than 6 months. We aimed to assess the response to single-agent selinexor, an oral selective inhibitor of nuclear export, in patients with relapsed or refractory DLBCL who had no therapeutic options of potential clinical benefit., Methods: SADAL was a multicentre, multinational, open-label, phase 2b study done in 59 sites in 19 countries. Patients aged 18 years or older with pathologically confirmed diffuse large B-cell lymphoma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received two to five lines of previous therapies, and progressed after or were not candidates for autologous stem-cell transplantation were enrolled. Germinal centre B-cell or non-germinal centre B-cell tumour subtype and double or triple expressor status were determined by immunohistochemistry and double or triple hit status was determined by cytogenetics. Patients received 60 mg selinexor orally on days 1 and 3 weekly until disease progression or unacceptable toxicity. The study was initially designed to evaluate both 60 mg and 100 mg twice-weekly doses of selinexor; however, the 100 mg dose was discontinued in the protocol (version 7.0) on March 29, 2017, when an improved therapeutic window was observed at 60 mg. Primary outcome was overall response rate. The primary outcome and safety were assessed in all patients who received 60 mg selinexor under protocol version 6.0, or enrolled under protocol versions 7.0 or higher and received at least one dose of selinexor. This trial is registered at ClinicalTrials.gov, NCT02227251 (active but not enrolling)., Findings: Between Oct 21, 2015, and Nov 2, 2019, 267 patients were randomly assigned, with 175 allocated to the 60 mg group and 92 to the discontinued 100 mg group. 48 patients assigned to the 60 mg group were excluded due to enrolment before version 6.0 of the protocol; the remaining 127 patients received selinexor 60 mg and were included in analyses of primary outcome and safety. The overall response rate was 28% (36/127; 95% CI 20·7-37·0); 15 (12%) achieved a complete response and 21 (17%) a partial response. The most common grade 3-4 adverse events were thrombocytopenia (n=58), neutropenia (n=31), anaemia (n=28), fatigue (n=14), hyponatraemia (n=10), and nausea (n=8). The most common serious adverse events were pyrexia (n=9), pneumonia (n=6), and sepsis (n=6). There were no deaths judged as related to treatment with selinexor., Interpretation: Single-drug oral selinexor induced durable responses and had a manageable adverse events profile in patients with relapsed or refractory DLBCL who received at least two lines of previous chemoimmunotherapy. Selinexor could be considered a new oral, non-cytotoxic treatment option in this setting., Funding: Karyopharm Therapeutics Inc., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
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- 2020
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