MCL

SOHO 2019 | Standard of care in mantle cell lymphoma

During the Society of Hematologic Oncology (SOHO) annual meeting, in Houston, US, a session on mantle cell lymphoma (MCL) was held. Doctor (Dr.) Anita Kumar, Memorial Sloan Kettering Cancer Center, New York, US, presented a talk entitled “Who Is a Candidate for Watch and Wait Therapy” in MCL1 and Professor (Prof.) Simon Rule, Derriford Hospital, Plymouth Hospitals NHS Trust, Plymouth, UK, gave two presentations; the first was on front-line therapy2 and the second on options for salvage therapy for patients with relapsed/refractory (R/R) MCL.3 This article provides a comprehensive summary of these talks regarding the current standard of care (SOC) for patients with MCL.

Who is a candidate for watch and wait therapy in MCL?1

This presentation by Dr. Kumar aimed to define which subgroup of patients with MCL are candidates for watch and wait therapy, as opposed to upfront treatment. A study by Martin et al.4, showed that observation was an acceptable option for patients with newly diagnosed MCL. In this study, 32% of patients were successfully monitored for over three months, with no adverse impact on overall survival (OS) through deferring therapy. The OS improved in the observation group compared to the treatment group, though the authors attributed this to the preferable disease biology of the patient group.4

Having established this, the question of how to identify the appropriate patients for observation remains. To determine this, it is necessary to look at the clinical and biological features of patients successfully observed. There are two subtypes of MCL:1

  1. Classical: associated with SOX-11 mutation, unmutated IGHV and a more genetically unstable profile
  2. Non-nodal leukemic: no SOX-11 mutation, hypermutated IGHV and a more genetically stable profile

Additionally, there are known prognostic factors in MCL associated with OS, though these do not necessarily indicate the need for treatment (Table 1).

Table 1. Prognostic factors in MCL1

Type of prognostic factor

Prognostic factor

Clinical

MCL International Prognostic Index (MIPI) score (incorporating; age, lactate dehydrogenase [LDH] level, performance status and white blood cell [WBC] count)

B-cell symptoms

Radiographic

SUVmax

PET features

Pathologic

Blastoid or pleomorphic

Proliferative signature

SOX-11 status

IGHV mutation status

Karyotype

Genomic alterations e.g. TP53, deletion 17, NOTCH 1/2

Dr. Kumar proceeded to present results from a study at Memorial Sloan Kettering Cancer Center, which aimed at describing the clinical and biological characteristics of patients with MCL who were either observed or treated and evaluated their subsequent outcomes. The hypothesis was that patients should be observed, or treated, based on clinical presentation and that negative prognostic features such as TP53mut should not exclude a patient from observation.

  • Patients with newly diagnosed MCL (n= 404)
    • Treated: 314 patients
    • Observed: 90 patients
      • Observation was defined as treatment deferral for at least three months post-diagnosis
      • Reasons for observation included lack of symptoms, low disease burden, absence of SOX-11 expression and disease limited to the gastrointestinal (GI) tract
  • There were some significant differences in patient characteristics between treatment arms including B-symptoms, blastoid/pleomorphic histology, Ki67, LDH/ULN ratio and leukemic phase disease
  • Median time of observation was 23 months
  • The only significant factor associated with a shorter time of observation was lymphadenopathy
  • Three patients with TP53mut were observed for four, 18 and 20 months

In patients observed for over two years (n =30), there were three clinical categories;

  1. Leukemic phase disease with minimal nodal disease +/- splenomegaly (n= 9)
  2. Low-tumor burden disease without leukemic phase disease (n= 17)
  3. GI tract-only disease (n= 4)

The study showed that observation did not have a negative impact on median OS (observation vs treatment: 11.4 vs 9.4 years).

Dr. Kumar and colleagues concluded:

  • One in five patients with newly diagnosed MCL could be observed
  • Of patients who were clinically selected for observation, 93% were successfully monitored for over six months with a median period of observation of 23 months
  • The presence of TP53 also did not exclude patients from being observed
  • There were no clear pathologic or biological features to exclude patients from observation

Therefore, Dr Kumar recommended that clinical criteria should drive the selection of patients fit for observation compared to upfront treatment.

Front-line therapy for MCL in 20192

Prof. Rule began his presentation by discussing the current treatment pathway for patients with MCL, explaining that the first evaluation to be made, is whether the patient requires therapy. If the answer is yes, the patient is then assessed for eligibility for autologous stem cell transplant (ASCT). If they are fit for ASCT, the current treatment algorithm recommends induction with rituximab (R) plus a high-dose (HD)-cytarabine-containing regimen, followed by ASCT. If the patient achieves a complete response (CR) or partial response (PR), maintenance should be given.

If the patient is not fit for ASCT, they are assessed for eligibility for cyclophosphamide (C), doxorubicin, vincristine, and prednisone (P; CHOP) therapy. If they are eligible, CHOP- or bendamustine (benda)-based therapy is given, followed by maintenance with R. If they are not, R-benda, R-C + vincristine + P (R-CVP) or R-chlorambucil (R-Cbl) is given, followed by maintenance.

As discussed by Dr. Kumar, patients who do not require therapy are observed until they require treatment. At this point they are assessed for eligibility for ASCT and the treatment pathway above is assessed.

Induction therapy

  • R-benda and R-cytarabine are commonly used induction regimens for transplant eligible patients with MCL who are young and fit (<65 years old)
  • In a phase III study by Hermine et al.5, the use of HD-cytarabine as part of induction therapy prior to ASCT was shown to improve progression-free survival (PFS), but not OS5
    • R-CHOP + myeloablative radio-chemotherapy + ASCT (control group) versus R-CHOP or R-dexamethasone + HD-cytarabine + cisplatin (R-DHAP) + HD-cytarabine conditioning + ASCT (cytarabine group)
    • Results given as control (n= 234) vs cytarabine (n= 232)
      • Time to treatment failure: 3.9 vs 9.1 years, hazard ratio (HR): 0.56, p= 0.038
      • Median PFS from end of induction: 4.1 vs 8.8 years, HR: 0.52, p< 0.0001
    • Immunochemotherapy containing HD-cytarabine + ASCT should be considered SOC for young and fit patients with MCL undergoing transplant
  • Both R-benda and R-cytarabine + ASCT achieve high-rates of durable remissions, though further testing in comparative prospective trials is recommended
    • Using these sequentially may reduce the risk of prolonged thrombocytopenia post-ASCT

 The role of ASCT

  • ASCT has been shown to be beneficial in young patients with MCL, even in an era where monoclonal antibodies (mAbs) such as R, are available
    • A large retrospective study by Gerson et al.6, showed that median PFS was improved with ASCT in patients aged <65 years old
      • Median PFS (with vs without ASCT): 75 vs 44 months, p< 0.01
      • Multivariate analysis showed ASCT was associated with improved PFS, HR: 0.54, p< 0.01, but not OS
    • Additionally, ASCT remains important as part of therapy in first remission7
      • Randomized trial comparing consolidation with myeloablative radio-chemotherapy + ASCT to α-interferon (IFN) maintenance in first remission
      • Long-term follow-up of 14 years showed ASCT prolonged PFS and OS
        • Median PFS (ASCT vs IFN): 3.3 vs 1.5 years, p< 0.0001
        • Median OS (ASCT vs IFN): 7.5 vs 4.8 years, p= 0.019

Maintenance

  • Maintenance with R should be the SOC for young, transplant eligible patients:8
    • LYMA trial investigated maintenance with R, after ASCT in young patients with MCL
      • Induction: R-DHAP (four courses) + ASCT + consolidation
      • Patients not in response after R-DHAP received four courses of R-CHOP prior to ASCT
      • Conditioning: R + BCNU + etoposide + aracytine + melphalan (R-BEAM)
      • Patients in response post-ASCT were randomized to maintenance with R (n= 120), or no maintenance (n= 120)
    • Results below are given as maintenance with R vs no maintenance:
      • Median event-free survival (EFS) from randomization: not reached (NR) vs NR
      • Four-year EFS: 78.9% vs 61.4%, p= 0.0012
      • Four-year PFS from randomization: 82.2% vs 64.6%, p= 0.0005
      • Four-year OS from randomization: 88.7% vs 81.4%, p= 0.0413
      • Patients who received R maintenance compared to those who did not, had:
        • 54.3% reduction in risk of event
        • 60% reduction in risk of progression
        • 50% reduction in risk of death
  • Maintenance with lenalidomide:
    • Ladetto et al.9 investigated the use of lenalidomide as maintenance, compared to observation alone in young patients, in a phase III prospective, randomized trial
      • Three rounds of R-CHOP, R + HD cyclophosphamide, two cycles of R + HD-cytarabine
      • Conditioning: BEAM
      • After ASCT, patients were randomized to lenalidomide maintenance (n= 104) or observation (n= 101)
      • In the lenalidomide maintenance arm, 53/104 did not start or complete maintenance due to death, compared to 32/101 in the observation arm
      • Additionally, 28% of patients received <25% of the planned lenalidomide dose
      • Three-year PFS (lenalidomide vs observation): 80% vs 64%, HR: 0.51
      • OS curves were superimposable
      • Grade 3­–4 hematological toxicity (lenalidomide vs observation): 63% vs 11%
      • Whilst lenalidomide maintenance may have a role post-ASCT in young patients with MCL, there are some limitations to applicability
    • Prof. Rule noted that the issue with lenalidomide is that it is often given at a too high dose, causing additional toxicity

Prof. Rule noted that the only maintenance that has been proven to be efficacious in this patient population, is R.

Patients with TP53mut status

  • Patients with the TP53 mutation have particularly poor outcomes, as demonstrated by Eskelund et al.10
    • Evaluated prognostic impact of recurrent genetic aberrations
    • TP53mut was significantly associated with inferior outcome in univariate analysis and remained prognostic for OS and time to relapse in multivariate analysis
    • Median OS (TP53mut vs TP53wt): 1.8 vs 12.7 years
    • These patients respond poorly to regimens including R or cytarabine and ASCT
    • These patients should be considered for experimental frontline trials of novel agents
  • Patients with TP53mut represent an unmet need
  • Prof. Rule added that he would consider an upfront allogeneic stem cell transplant (allo-SCT) in this subgroup

 Patients not eligible for transplant, fit for CHOP therapy

There are four main therapy choices for patients who are ineligible for transplant, but who are eligible for CHOP therapy:

  1. R-CHOP
  2. VR-CAP (R-CHOP with bortezomib in place of vincristine)
  3. R-benda
  4. R + benda + cytarabine 500 (RBAC500)

R-CHOP versus VR-CAP11

  • The substitution of vincristine for bortezomib in the R-CHOP regimen (VR-CAP) has shown impressive activity in patients with MCL who are not eligible for transplant
    • Six–eight cycles of R-CHOP or VR-CAP
    • Median PFS (R-CHOP vs VR-CAP): 14.4 vs 24.7 months (HR: 0.63, favoring VR-CAP, p< 0.001)
    • Four-year OS rate: 54% vs 64%
    • VR-CAP was more effective than R-CHOP, however there were higher rates of neutropenia and thrombocytopenia
  • Prof. Rule recommended that CHOP therapies incorporate the use of subcutaneous (SC) bortezomib once weekly

RBAC500 regimen12

  • A phase II trial by Visco et al.12 showed the RBAC500 regimen was efficacious in elderly patients with MCL
    • Overall response rate (ORR): 96%
    • CR rate: 93%
    • Two-year PFS: 81%
    • Two-year OS: 85%
  • Historically, this regimen caused significant hematological toxicity, however in this phase II trial, RBAC500 was safely administered in the frontline setting with reduced hematologic toxicity

Frontline ibrutinib + R (IR)

  • The combination of IR was investigated in a phase II trial13
    • Previously untreated elderly (>65 years) patients with MCL (n= 42)
    • Best ORR: 95%
    • Median cycles of IR to reach CR: 4
    • PET-based CR (n = 32): 100%
    • Measurable residual disease (MRD)-negativity by flow cytometry: 65%
    • Median PFS and OS: NR
    • Represents a safe and effective frontline treatment for elderly patients with MCL
  • Randomized trials are required to demonstrate efficacy of IR
    • ENRICH is a phase III UK-based trial: of IR vs R-chemotherapy in elderly patients with MCL that is ongoing2
    • Triangle is a European MCL Network phase III trial with three arms:14
      • Arm 1: SOC treatment of three cycles of R-CHOP alternated with three cycles of R-DHAP followed by ASCT
      • Arm 2: as per Arm 1 with ibrutinib given with R-CHOP chemotherapy, and two years of maintenance with ibrutinib after ASCT
      • Arm 3: R-CHOP with ibrutinib, alternating with R-DHAP as per Arm 1 but with direct ibrutinib maintenance without ASCT

To summarize, Prof. Rule noted that patients should be treated when clinically indicated, and that in young patients, cytarabine is key to intensive treatments, with rituximab maintenance. For older patients, CHOP- and benda-based treatments are advisable, though he added that novel agents are rapidly moving into the frontline setting and will likely form part of the SOC.

Novel salvage therapy for MCL3

In his second talk, Prof. Rule began by noting the five currently available therapies for the treatment of R/R MCL:

  • Ibrutinib – a Burton’s tyrosine kinase (BTK) inhibitor
  • Bortezomib – a proteasome inhibitor (PI)
  • Lenalidomide – an immunomodulatory drug (IMiD)
  • Temsirolimus – an mTOR inhibitor
  • Acalabrutinib – a BTK inhibitor

Prof. Rule then discussed other potential therapies developed for MCL, with varying degrees of success (Table 2). He noted that many of these drugs have not been tested in patients who previously received BTK inhibitors, which is a limitation of these investigations.

Table 2. Therapies investigated for the treatment of R/R MCL15-20

Drug/ combination

Drug type

Study

Conclusion

Idelalisib15

Phosphoinositide 3-kinase (PI3K) inhibitor

Phase I

ORR: 40% (16/40)

CR: 5% (2/40)

Median duration of response (DoR): 2.7 months

Median PFS: 3.7 months

One-year PFS: 22%

Prof. Rule stated this is not a clinically superior therapy 

Umbralisib (TGR-1202) + ibrutinib16

PI3K inhibitor

Phase I/Ib

ORR: 67%

PR: 6/9

Median time on study: 10.9 months

Prof. Rule questioned whether the addition of umbralisib enhanced the activity of ibrutinib significantly

Palbociclib + ibrutinib17

Cyclin-dependent kinase (CDK) inhibitor

Phase I

ORR: 67%

CR: 37%

Two-year PFS: 59.4%

Dose-limiting toxicity: grade 3 rash

Phase II study ongoing  

Entospletinib (GS-9973)18

Spleen tyrosine kinase inhibitor

Phase II

PFS at 16 weeks: 63.9%

ORR: 17.9%

Limited single agent activity

R + lenalidomide19

mAb + IMiD

Phase I/II

Grade 3-4 hematological toxicity: neutropenia (66%), lymphopenia (36%), leucopenia (30%) and thrombocytopenia (23%)

ORR: 57%

CR: 36%

Median DoR: 18.9 months

Median PFS: 11.1 months

Median OS: 24.3 months

Bortezomib + lenalidomide20

PI + IMiD

Phase II

CR: 15%

PR: 25%

One-year PFS: 40%

One-year EFS: 25%

One-year OS: 68%

Combination not pursued further

Therefore, Prof. Rule stated that BTK inhibitors are the best options for patients with R/R MCL based on the ORR and CR rates shown in Table 3.

Table 3. Response rates to BTK inhibitors21-24

 

N

ORR (%)

CR (%)

Median DoR (months)

Median PFS (months)

Median prior lines of therapy

Ibrutinib21

111

68

21

17.5

13.9

3

Acalabrutinib22

124

81

40

Not reached

Not reached

2

Tirabrutnib23

16

92

46

Not reported

Not reported

3

Zanubrutinib24

37

87

30

14.7

15.4*

1*

* For total cohort; including patients with treatment naïve disease (n= 8) and R/R disease (n= 37)

A recent study by Kumar et al.25 showed median OS and PFS decreases after each subsequent line of therapy (Table 4), and early treatment failure after first line therapy is associated with poorer OS.25 Prof. Rule therefore noted that using the most effective options upfront and at first relapse is crucial.3

Table 4. Decreasing responses to each line of therapy in patients with MCL25

Line of therapy

OS

PFS

First

9.7 years

4 years

Second

41.1 months

14 months

Third

25.2 months

6.5 months

Fourth

14.4 months

5 months

Novel targets and combinations

Prof. Rule noted that there are many other novel therapies under investigation, including epigenetic modulators such as cladribine, mTOR inhibitors like temsirolimus and chimeric antigen receptor (CAR) T cell therapies. Prof. Rule added that data on CAR T in MCL is due to be presented in upcoming congresses, and it could have a role in treatment following the use of BTK inhibitors.3

There are also many ongoing trials in the R/R MCL setting, for example; ibrutinib in combination with various agents such as bortezomib, selinexor, ixazomib, lenalidomide + R, and venetoclax, with an aim of further increasing efficacy. Additionally, other combinations are being investigated such as venetoclax with BR, ixazomib + R and benda + obinutuzumab.3

Patients with TP53mut status

For R/R patients with TP53mut status, outcomes with ibrutinib are less favorable compared to patients with TP53wt (Table 5).26

Table 5. Responses to ibrutinib by TP53 mutation status26

 

Median PFS (months)

Median OS (months)

ORR (%)

TP53wt

12

33.6

70.2

TP53mut

4

10.3

55

The PHILEMON study, investigating the use of ibrutinib with lenalidomide and R, has shown a 64% complete remission rate in patients with TP53mut. These promising results indicate this regimen may be able to overcome the negative prognostic feature of TP53mut:3

  • TP53wt:
    • ORR: 79% (30/38)
    • CR: 55% (21/38)
  • TP53mut
    • ORR: 73% (8/11)
    • CR: 64% (7/11)

Venetoclax

Prof. Rule lastly discussed the use of venetoclax for R/R MCL:

  • Venetoclax after BTK inhibitor therapy: ORR of 60% in 20 patients previously treated with BTK inhibitors, however median PFS was 2.6 months and median OS was 4.3 months27
  • Venetoclax + ibrutinib: the phase II AIM study28 showed a benefit of ibrutinib + venetoclax therapy, particularly in patients with TP53mut:
    • CR at week 16 (n= 24): 42%
    • CR in patients with TP53mut (n = 12): 50% (n= 6)
      • Five of six patients with a CR remained progression-free for 13–20 months at time of analysis
  • Venetoclax + ibrutinib + obinutuzumab: the phase I OAsis study29 is investigating this combination, which Prof. Rule believes to be a promising option. Data are expected to be presented at the American Society of Hematology (ASH) meeting later this year

Conclusion

Prof. Rule concluded that combination therapy with a BTK inhibitor is the future of therapy for R/R MCL, and that MRD-status may help guide treatment decisions in future, potentially dictating when to stop treatment, and helping to identify the most appropriate treatment options.

References
  1. Kumar A. Who Is a Candidate for Watch and Wait Therapy? Oral presentation. 2019 Sep 13. SOHO annual meeting, Houston, US.
  2. Rule S. What is the standard front-line therapy for MCL? Oral presentation. 2019 Sep 13. SOHO annual meeting, Houston, US.
  3. Rule S. Novel salvage therapy. Oral presentation. 2019 Sep 13. SOHO annual meeting, Houston, US.
  4. Martin P. et al. Outcome of Deferred Initial Therapy in Mantle-Cell Lymphoma. J Clin Onc. 2009 Feb 02. DOI: 10.1200/JCO.2008.19.6121
  5. Hermine O.  et al. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet. 2016 Jun 13. DOI: 10.1016/S0140-6736(16)00739-X
  6. Gerson J.N. et al. Survival Outcomes of Younger Patients With Mantle Cell Lymphoma Treated in the Rituximab Era. 2019 Jan 07. J Clin Onc. DOI: 10.1200/JCO.18.00690
  7. Zoellner A. et al. Autologous stem cell transplantation in first remission significantly prolongs progression-free and overall survival in mantle cell lymphoma. International Congress on Malignant Lymphomas (ICML). 2019 Jun. Abstract #013 and oral presentation
  8. Le Gouill S. et al. Rituximab maintenance after autologous stem cell transplantation prolongs survival in younger patients with mantle cell lymphoma: final results of the randomized phase 3 LYMA trial of the Lysa/Goelams Group. Blood. 2016 Dec 01.http://www.bloodjournal.org/content/128/22/145 [Accessed 2019 Oct 01]
  9. Ladetto M. et al. Lenalidomide Maintenance after Autologous Transplantation Prolongs PFS in Young MCL Patients: Results of the Randomized Phase III MCL 0208 Trial from Fondazione Italiana Linfomi (FIL). Blood. 2018 Nov 21. DOI: 10.1182/blood-2018-99-110289
  10. Eskelund C.W. et al. TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. Blood. 2017 Oct 26. DOI: 10.1182/blood-2017-04-779736
  11. Robak T. et al. Bortezomib-Based Therapy for Newly Diagnosed Mantle-Cell Lymphoma. N Eng J Med. 2015 Mar 05. DOI: 10.1056/NEJMoa1412096
  12. Visco C. et al. Rituximab, Bendamustine and Cytarabine (RBAC500) As Induction Therapy in Elderly Patients with Mantle Cell Lymphoma: Final Results of a Phase 2 Study from the Fondazione Italiana Linfomi. Blood. 2016 Dec 01.http://www.bloodjournal.org/content/128/22/472 [Accessed 2019 Oct 01]
  13. Jain P. et al. Combination of ibrutinib with rituximab is highly effective in previously untreated elderly (>65 years) patients (pts) with mantle cell lymphoma (MCL) – phase II trial. International Congress on Malignant Lymphomas (ICML). 2019 Jun. Abstract #011 and oral presentation
  14. Cancer Research UK & UCL Cancer Trials Centre: Triangle.https://www.ctc.ucl.ac.uk/TrialDetails.aspx?Trial=133&TherA=4 [Accessed 2019 Oct 01]
  15. Spurgeon S.E.F. et al. Final results of a phase I study of idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase P110δ (PI3Kδ), in patients with relapsed or refractory mantle cell lymphoma (MCL). J Clin Onc. 2017 Jan 30. DOI: 10.1200/jco.2013.31.15_suppl.8519
  16. Davids M.S. et al. TGR-1202 in Combination with Ibrutinib in Patients with Relapsed or Refractory CLL or MCL: Preliminary Results of a Multicenter Phase I/Ib Study. Blood. 2016 Dec 01.http://www.bloodjournal.org/content/128/22/641 [Accessed 2019 Oct 01]
  17. Martin P. et al. A phase 1 trial of ibrutinib plus palbociclib in previously treated mantle cell lymphoma. Blood. 2019 Mar 14. DOI: 10.1182/blood-2018-11-886457
  18. Andorsky D.J. et al. An open‐label phase 2 trial of entospletinib in indolent non‐Hodgkin lymphoma and mantle cell lymphoma. Br J Hem. 2018 Sep 05. DOI: 10.1111/bjh.15552
  19. Wang M. et al. Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial. Lancet Onc. 2012 Jun 06. DOI: 10.1016/S1470-2045(12)70200-0
  20. Morrison V.A. et al. Therapy with bortezomib plus lenalidomide for relapsed/refractory mantle cell lymphoma: final results of a phase II trial (CALGB 50501). Leuk & Lymph. 2014 Jul 04. DOI: 10.3109/10428194.2014.938333
  21. Wang M. et al.  Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma. N Eng J Med. 2013 Aug 03. DOI: 10.1056/NEJMoa1306220
  22. Wang M. et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2017 Dec 11. DOI: 10.1016/S0140-6736(17)33108-2
  23. Walter H.S. et al. A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies. Blood. 2016. DOI: 10.1182/blood-2015-08-664086
  24. Tam C.S.L. et al. Updated safety and efficacy data in the phase I trial of patients with mantle cell lymphoma (MCL) treated with bruton tyrosine kinase (BTK) inhibitor zanubritinib (BGB-3111). Hem Onc. 2019 Jun 12. DOI: 10.1002/hon.55_2630
  25. Kumar A. et al. Patterns of survival in patients with recurrent mantle cell lymphoma in the modern era: progressive shortening in response duration and survival after each relapse. Blood Cancer J. 2019 May 20. DOI: 10.1038/s41408-019-0209-5
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  29. Le Gouill S. et al. OAsis: An international phase I trial of obinutuzumab, venetoclax plus ibrutinib in relapsed/refractory mantle cell lymphoma. J Clin Onc. 2017 May 11. DOI: 10.1200/JCO.2016.34.15_suppl.TPS7583

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