Letter to the Editor

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Blood Res 2021; 56(4):

Published online December 31, 2021

https://doi.org/10.5045/br.2021.2020322

© The Korean Society of Hematology

Tp53 disruptions: is there a marker of poor prognosis in chronic lymphoproliferative disorders?

Emanuele Cencini, Alberto Fabbri, Donatella Raspadori, Alessandro Gozzetti, Monica Bocchia

Unit of Hematology, Azienda Ospedaliera Universitaria Senese & University of Siena, Siena, Italy

Correspondence to : Emanuele Cencini
Unit of Hematology, University Hospital, Azienda Ospedaliera Universitaria Senese & University of Siena, Viale Bracci - 53100 Siena, Italy
E-mail: cencioema@libero.it

Received: December 16, 2020; Revised: July 6, 2021; Accepted: August 25, 2021

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

TO THE EDITOR: We read with great interest the paper by Göçer and Kurtoğlu about a real-life experience of 32 patients with chronic lymphocytic leukemia (CLL, 11/32 cases) or B-cell non-Hodgkin lymphomas (NHL, 21/32 cases) treated with ibrutinib [1]. The authors observed an elevated overall response rate (ORR) and complete response (CR) rate, consistent with available literature data. Overall toxicity was manageable without unexpected adverse events (AE). In all the 11 CLL patients, the deletion of 17p (del17p) mutation was assessed and 4 were positive. Interestingly, a survival curve for overall survival (OS) according to del17p status was performed and showed that in four mutated cases, one had early disease relapse, while the others were disease-free, despite the short follow-up period [1]. We agree with the authors that single-agent ibrutinib is a suitable option for patients with both CLL and NHL, regardless of prior therapies and disease subtype. We strongly appreciate the effort to present a real-world experience on ibrutinib use for NHL patients, including marginal zone lymphoma (MZL), an NHL subtype in which ibrutinib is not approved as treatment in most countries. However, we did not find any mention about del17p or TP53 mutations for NHL cases, even if the TP53 gene could have a prognostic significance in lymphoid malignancies other than CLL. It is interesting to assess TP53 disruptions (17p deletions and/or TP53 mutations) in NHL cases experiencing an early disease progression during or after ibrutinib therapy.

Chronic lymphoproliferative disorders such as MZL are characterized by an indolent course. Rituximab with bendamustine (BR) or alkylating agents as first-line regimens demonstrated long-term efficacy and mild toxicity. However, a small proportion of refractory patients exists and there is a lack of clinical trials to establish the optimal management for this subgroup [2]. Poor prognosis has been associated with TP53 disruptions in many solid tumors and hematological malignancies, including lung cancer and splenic MZL (SMZL) [3]. Noy and colleagues demonstrated the possibility of achieving a durable response with ibrutinib single-agent in relapsed/refractory (R/R) MZL in the PCYC-1121 phase II trial, leading to the Food and Drugs (FDA) approval of ibrutinib for previously treated MZL patients [4, 5]. However, in the PCYC-1121 study, only 14 SMZL cases were enrolled. Göçer and Kurtoğlu also did not specify the MZL subtype in their cohort. Moreover, to our knowledge, only a case of extranodal MZL and 5 cases with central nervous system MZL localization receiving ibrutinb were published. Thus, a real-life experience about SMZL is lacking [1, 4-7].

At our institution, we managed a 17p-deleted, rituximab-refractory SMZL patient with concomitant lung cancer. The patient started first-line therapy with BR and after 4 cycles, CT scan showed normal spleen size and a pulmonary lesion. Histological exam of the lesion after lobectomy demonstrated squamous lung cancer (pT2a-pN0, PDL1-negative, ALK-negative, EGFR not assessed). The patient stopped BR and underwent clinical follow-up for both malignancies. Nine months later, the patient relapsed. Due to this unusual behavior, FISH analysis was performed and revealed a 17p deletion. Karyotype did not show other alterations. We decided to administer a chemotherapy-free regimen using bortezomib and rituximab. A partial response was obtained after 3 cycles; however, CT scan showed lung cancer recurrence. The patient then received platinum-based therapy. However, at oncological restaging, he had lymphocytosis and thrombocytopenia, and CT scan demonstrated stable disease, an increase of spleen size, and enlarged lymph nodes suspicious for a lymphoproliferative disorder. Given the 17p deletion-positive status, we decided to treat the patient with ibrutinib. We obtained the drug for compassionate use after the approval of Institutional Review Board. The patient signed the informed consent form and received 560 mg ibrutinib orally once daily. Spleen size rapidly diminished during the clinical exam and platelet count improved. Although the SMZL clinically improved during the first cycle, the patient developed worsening respiratory failure and underwent sudden death at home, probably due to the concomitant pulmonary neoplasm; autopsy was not performed.

Lymphoproliferative disorders and solid neoplasms with 17p deletion are characterized by poor prognosis with no standard of care, representing an unmet need for clinicians [3, 8]. Interestingly, the presence of TP53 mutations was associated with response to anlotinib, a novel oral multi-targeted antiangiogenic tyrosine kinase inhibitor used in advanced, non-small cell lung cancer [9]. Moreover, the selective antitumor activity of ibrutinib, an oral BTK inhibitor, was demonstrated in EGFR-mutant non-small cell lung cancer cells [10].

Ibrutinib is highly effective in CLL patients; however, long-term follow-up data showed that patients with TP53 disruptions tend to lose their response. A recently published paper demonstrated a lower capacity of inducing apoptosis on TP53-disrupted CLL cells compared to wild type CLL cells [11, 12]. For B-cell lymphoid malignancies with 17p deletion and/or TP53 mutations, different approaches are currently being tested, such as the use of BTK inhibitors, PI3K inhibitors, and BCL2 inhibitors. Thus, we strongly encourage to test del17p status in R/R patients with CLL or NHL [11-15]. The PI3K inhibitor duvelisib was successfully administered to patients with R/R indolent non-Hodgkin lymphomas (NHL), but it is not available for these malignancies in many countries outside clinical trials [13]. In a phase II trial by Noy and colleagues, ibrutinib gave promising results in previously treated MZL cases, whose responses were recently confirmed after a long-term follow-up analysis [4, 5]. The long-term analysis after a median follow-up of 33 months confirmed the efficacy and safety of ibrutinib in 63 R/R MZL cases; ORR was 58%, and median progression-free survival (PFS) and duration of response (DOR) were 15.7 and 27.6 months, respectively [4, 5]. Remarkably, in an exploratory analysis, even if TP53 was not mentioned, about 1400 cancer genes and 200 microRNA were investigated for a possible association with response and survival, including MYD88, A20, CARD11, KMT2D, and NOTCH-2. MYD88 mutation was associated with improved PFS, while mutations in KMT2D and CARD11 were associated with inferior DOR compared to wild type. NOTCH-2 did not show an association with response or survival [5].

In conclusion, ibrutinib achieved FDA approval for R/R MZL but it is not yet approved in most countries. It should be considered as a new treatment option, especially for MZL or other indolent NHL patients harboring 17p deletion and/or TP53 mutations which represent a subgroup characterized by dismal prognosis.

Authors’ Disclosures of Potential Conflicts of Interest


No potential conflicts of interest relevant to this article were reported.

  1. Göçer M, Kurtoğlu E. Safety and efficacy analysis of ibrutinib in 32 patients with CLL and various B-cell lymphomas: real-world data from a single-center study in Turkey. Blood Res 2020;55:206-12.
    Pubmed KoreaMed CrossRef
  2. Zucca E, Arcaini L, Buske C, et al. Marginal zone lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2020;31:17-29.
    Pubmed CrossRef
  3. Tessoulin B, Eveillard M, Lok A, et al. p53 dysregulation in B-cell malignancies: more than a single gene in the pathway to hell. Blood Rev 2017;31:251-9.
    Pubmed CrossRef
  4. Noy A, de Vos S, Thieblemont C, et al. Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma. Blood 2017;129:2224-32.
    Pubmed KoreaMed CrossRef
  5. Noy A, de Vos S, Coleman M, et al. Durable ibrutinib responses in relapsed/refractory marginal zone lymphoma: long-term follow-up and biomarker analysis. Blood Adv 2020;4:5773-84.
    Pubmed KoreaMed CrossRef
  6. Furqan F, Watson G, Samaniego F, et al. Ibrutinib-based therapy for the treatment of marginal zone lymphoma with central nervous system involvement. Leuk Lymphoma 2020;61:2980-4.
    Pubmed KoreaMed CrossRef
  7. Lynch RC, Advani RH. Dramatic response with single-agent ibrutinib in multiply relapsed marginal zone lymphoma with MYD88L265P mutation. Case Rep Oncol 2017;10:813-8.
    Pubmed KoreaMed CrossRef
  8. Zhao L, Qu X, Wu Z, Li Y, Zhang X, Guo W. TP53 somatic mutations are associated with poor survival in non-small cell lung cancer patients who undergo immunotherapy. Aging (Albany NY) 2020;12:14556-68.
    Pubmed KoreaMed CrossRef
  9. Fang S, Cheng W, Zhang M, Yang R. Association of TP53 mutations with response to anlotinib treatment in advanced non-small cell lung cancer. Onco Targets Ther 2020;13:6645-50.
    Pubmed KoreaMed CrossRef
  10. Gao W, Wang M, Wang L, et al. Selective antitumor activity of ibrutinib in EGFR-mutant non-small cell lung cancer cells. J Natl Cancer Inst 2014;106:dju204.
    Pubmed KoreaMed CrossRef
  11. O'Brien S, Furman RR, Coutre S, et al. Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood 2018;131:1910-9.
    Pubmed KoreaMed CrossRef
  12. Guarini A, Peragine N, Messina M, et al. Unravelling the suboptimal response of TP53-mutated chronic lymphocytic leukaemia to ibrutinib. Br J Haematol 2019;184:392-6.
    Pubmed CrossRef
  13. Rule S, Dreyling M, Goy A, et al. Ibrutinib for the treatment of relapsed/refractory mantle cell lymphoma: extended 3.5-year follow up from a pooled analysis. Haematologica 2019;104:211-4.
    Pubmed KoreaMed CrossRef
  14. Flinn IW, Miller CB, Ardeshna KM, et al. DYNAMO: a phase II study of duvelisib (IPI-145) in patients with refractory indolent non-hodgkin lymphoma. J Clin Oncol 2019;37:912-22.
    Pubmed CrossRef
  15. Eyre TA, Walter HS, Iyengar S, et al. Efficacy of venetoclax monotherapy in patients with relapsed, refractory mantle cell lymphoma after Bruton tyrosine kinase inhibitor therapy. Haematologica 2019;104:e68-71.
    Pubmed KoreaMed CrossRef

Article

Letter to the Editor

Blood Res 2021; 56(4): 333-334

Published online December 31, 2021 https://doi.org/10.5045/br.2021.2020322

Copyright © The Korean Society of Hematology.

Tp53 disruptions: is there a marker of poor prognosis in chronic lymphoproliferative disorders?

Emanuele Cencini, Alberto Fabbri, Donatella Raspadori, Alessandro Gozzetti, Monica Bocchia

Unit of Hematology, Azienda Ospedaliera Universitaria Senese & University of Siena, Siena, Italy

Correspondence to:Emanuele Cencini
Unit of Hematology, University Hospital, Azienda Ospedaliera Universitaria Senese & University of Siena, Viale Bracci - 53100 Siena, Italy
E-mail: cencioema@libero.it

Received: December 16, 2020; Revised: July 6, 2021; Accepted: August 25, 2021

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Body

TO THE EDITOR: We read with great interest the paper by Göçer and Kurtoğlu about a real-life experience of 32 patients with chronic lymphocytic leukemia (CLL, 11/32 cases) or B-cell non-Hodgkin lymphomas (NHL, 21/32 cases) treated with ibrutinib [1]. The authors observed an elevated overall response rate (ORR) and complete response (CR) rate, consistent with available literature data. Overall toxicity was manageable without unexpected adverse events (AE). In all the 11 CLL patients, the deletion of 17p (del17p) mutation was assessed and 4 were positive. Interestingly, a survival curve for overall survival (OS) according to del17p status was performed and showed that in four mutated cases, one had early disease relapse, while the others were disease-free, despite the short follow-up period [1]. We agree with the authors that single-agent ibrutinib is a suitable option for patients with both CLL and NHL, regardless of prior therapies and disease subtype. We strongly appreciate the effort to present a real-world experience on ibrutinib use for NHL patients, including marginal zone lymphoma (MZL), an NHL subtype in which ibrutinib is not approved as treatment in most countries. However, we did not find any mention about del17p or TP53 mutations for NHL cases, even if the TP53 gene could have a prognostic significance in lymphoid malignancies other than CLL. It is interesting to assess TP53 disruptions (17p deletions and/or TP53 mutations) in NHL cases experiencing an early disease progression during or after ibrutinib therapy.

Chronic lymphoproliferative disorders such as MZL are characterized by an indolent course. Rituximab with bendamustine (BR) or alkylating agents as first-line regimens demonstrated long-term efficacy and mild toxicity. However, a small proportion of refractory patients exists and there is a lack of clinical trials to establish the optimal management for this subgroup [2]. Poor prognosis has been associated with TP53 disruptions in many solid tumors and hematological malignancies, including lung cancer and splenic MZL (SMZL) [3]. Noy and colleagues demonstrated the possibility of achieving a durable response with ibrutinib single-agent in relapsed/refractory (R/R) MZL in the PCYC-1121 phase II trial, leading to the Food and Drugs (FDA) approval of ibrutinib for previously treated MZL patients [4, 5]. However, in the PCYC-1121 study, only 14 SMZL cases were enrolled. Göçer and Kurtoğlu also did not specify the MZL subtype in their cohort. Moreover, to our knowledge, only a case of extranodal MZL and 5 cases with central nervous system MZL localization receiving ibrutinb were published. Thus, a real-life experience about SMZL is lacking [1, 4-7].

At our institution, we managed a 17p-deleted, rituximab-refractory SMZL patient with concomitant lung cancer. The patient started first-line therapy with BR and after 4 cycles, CT scan showed normal spleen size and a pulmonary lesion. Histological exam of the lesion after lobectomy demonstrated squamous lung cancer (pT2a-pN0, PDL1-negative, ALK-negative, EGFR not assessed). The patient stopped BR and underwent clinical follow-up for both malignancies. Nine months later, the patient relapsed. Due to this unusual behavior, FISH analysis was performed and revealed a 17p deletion. Karyotype did not show other alterations. We decided to administer a chemotherapy-free regimen using bortezomib and rituximab. A partial response was obtained after 3 cycles; however, CT scan showed lung cancer recurrence. The patient then received platinum-based therapy. However, at oncological restaging, he had lymphocytosis and thrombocytopenia, and CT scan demonstrated stable disease, an increase of spleen size, and enlarged lymph nodes suspicious for a lymphoproliferative disorder. Given the 17p deletion-positive status, we decided to treat the patient with ibrutinib. We obtained the drug for compassionate use after the approval of Institutional Review Board. The patient signed the informed consent form and received 560 mg ibrutinib orally once daily. Spleen size rapidly diminished during the clinical exam and platelet count improved. Although the SMZL clinically improved during the first cycle, the patient developed worsening respiratory failure and underwent sudden death at home, probably due to the concomitant pulmonary neoplasm; autopsy was not performed.

Lymphoproliferative disorders and solid neoplasms with 17p deletion are characterized by poor prognosis with no standard of care, representing an unmet need for clinicians [3, 8]. Interestingly, the presence of TP53 mutations was associated with response to anlotinib, a novel oral multi-targeted antiangiogenic tyrosine kinase inhibitor used in advanced, non-small cell lung cancer [9]. Moreover, the selective antitumor activity of ibrutinib, an oral BTK inhibitor, was demonstrated in EGFR-mutant non-small cell lung cancer cells [10].

Ibrutinib is highly effective in CLL patients; however, long-term follow-up data showed that patients with TP53 disruptions tend to lose their response. A recently published paper demonstrated a lower capacity of inducing apoptosis on TP53-disrupted CLL cells compared to wild type CLL cells [11, 12]. For B-cell lymphoid malignancies with 17p deletion and/or TP53 mutations, different approaches are currently being tested, such as the use of BTK inhibitors, PI3K inhibitors, and BCL2 inhibitors. Thus, we strongly encourage to test del17p status in R/R patients with CLL or NHL [11-15]. The PI3K inhibitor duvelisib was successfully administered to patients with R/R indolent non-Hodgkin lymphomas (NHL), but it is not available for these malignancies in many countries outside clinical trials [13]. In a phase II trial by Noy and colleagues, ibrutinib gave promising results in previously treated MZL cases, whose responses were recently confirmed after a long-term follow-up analysis [4, 5]. The long-term analysis after a median follow-up of 33 months confirmed the efficacy and safety of ibrutinib in 63 R/R MZL cases; ORR was 58%, and median progression-free survival (PFS) and duration of response (DOR) were 15.7 and 27.6 months, respectively [4, 5]. Remarkably, in an exploratory analysis, even if TP53 was not mentioned, about 1400 cancer genes and 200 microRNA were investigated for a possible association with response and survival, including MYD88, A20, CARD11, KMT2D, and NOTCH-2. MYD88 mutation was associated with improved PFS, while mutations in KMT2D and CARD11 were associated with inferior DOR compared to wild type. NOTCH-2 did not show an association with response or survival [5].

In conclusion, ibrutinib achieved FDA approval for R/R MZL but it is not yet approved in most countries. It should be considered as a new treatment option, especially for MZL or other indolent NHL patients harboring 17p deletion and/or TP53 mutations which represent a subgroup characterized by dismal prognosis.

Authors’ Disclosures of Potential Conflicts of Interest


No potential conflicts of interest relevant to this article were reported.

References

  1. Göçer M, Kurtoğlu E. Safety and efficacy analysis of ibrutinib in 32 patients with CLL and various B-cell lymphomas: real-world data from a single-center study in Turkey. Blood Res 2020;55:206-12.
    Pubmed KoreaMed CrossRef
  2. Zucca E, Arcaini L, Buske C, et al. Marginal zone lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2020;31:17-29.
    Pubmed CrossRef
  3. Tessoulin B, Eveillard M, Lok A, et al. p53 dysregulation in B-cell malignancies: more than a single gene in the pathway to hell. Blood Rev 2017;31:251-9.
    Pubmed CrossRef
  4. Noy A, de Vos S, Thieblemont C, et al. Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma. Blood 2017;129:2224-32.
    Pubmed KoreaMed CrossRef
  5. Noy A, de Vos S, Coleman M, et al. Durable ibrutinib responses in relapsed/refractory marginal zone lymphoma: long-term follow-up and biomarker analysis. Blood Adv 2020;4:5773-84.
    Pubmed KoreaMed CrossRef
  6. Furqan F, Watson G, Samaniego F, et al. Ibrutinib-based therapy for the treatment of marginal zone lymphoma with central nervous system involvement. Leuk Lymphoma 2020;61:2980-4.
    Pubmed KoreaMed CrossRef
  7. Lynch RC, Advani RH. Dramatic response with single-agent ibrutinib in multiply relapsed marginal zone lymphoma with MYD88L265P mutation. Case Rep Oncol 2017;10:813-8.
    Pubmed KoreaMed CrossRef
  8. Zhao L, Qu X, Wu Z, Li Y, Zhang X, Guo W. TP53 somatic mutations are associated with poor survival in non-small cell lung cancer patients who undergo immunotherapy. Aging (Albany NY) 2020;12:14556-68.
    Pubmed KoreaMed CrossRef
  9. Fang S, Cheng W, Zhang M, Yang R. Association of TP53 mutations with response to anlotinib treatment in advanced non-small cell lung cancer. Onco Targets Ther 2020;13:6645-50.
    Pubmed KoreaMed CrossRef
  10. Gao W, Wang M, Wang L, et al. Selective antitumor activity of ibrutinib in EGFR-mutant non-small cell lung cancer cells. J Natl Cancer Inst 2014;106:dju204.
    Pubmed KoreaMed CrossRef
  11. O'Brien S, Furman RR, Coutre S, et al. Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood 2018;131:1910-9.
    Pubmed KoreaMed CrossRef
  12. Guarini A, Peragine N, Messina M, et al. Unravelling the suboptimal response of TP53-mutated chronic lymphocytic leukaemia to ibrutinib. Br J Haematol 2019;184:392-6.
    Pubmed CrossRef
  13. Rule S, Dreyling M, Goy A, et al. Ibrutinib for the treatment of relapsed/refractory mantle cell lymphoma: extended 3.5-year follow up from a pooled analysis. Haematologica 2019;104:211-4.
    Pubmed KoreaMed CrossRef
  14. Flinn IW, Miller CB, Ardeshna KM, et al. DYNAMO: a phase II study of duvelisib (IPI-145) in patients with refractory indolent non-hodgkin lymphoma. J Clin Oncol 2019;37:912-22.
    Pubmed CrossRef
  15. Eyre TA, Walter HS, Iyengar S, et al. Efficacy of venetoclax monotherapy in patients with relapsed, refractory mantle cell lymphoma after Bruton tyrosine kinase inhibitor therapy. Haematologica 2019;104:e68-71.
    Pubmed KoreaMed CrossRef
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