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R.A.L. de Groen et al.
were refractory to chemotherapy with R-CHOP (ritux- imab, cyclophosphamide, doxorubicin, vincristine and prednisone) (28%) compared with DLBCL patients who were chemosensitive (15%), but no statistically signifi- cant correlation with overall survival was found. The actual prognostic value of MYD88 in DLBCL requires fur- ther investigation, as other studies identified no effect of MYD88(L265P) on the survival of DLBCL patients.22, 112-114
In other subtypes of B-NHL, such as CLL, splenic mar- ginal zone lymphoma, and WM, MYD88(L265P9 is asso- ciated with a superior survival compared with wildtype MYD88.45,115,116 In WM, approximately 30-40% of patients present with concomitantly mutated MYD88 and CXCR4, a gene involved in homing of B cells in the bone marrow, and these patients present with a greater disease burden and reduced progression-free and overall
Table 2. Overview of several (ongoing) clinical trials with novel therapies targeting BTK, PI3K, mTOR and XPO1 in B-cell non-Hodgkin lymphomas in which MYD88(L265P) is frequent.
Medication Target
Ibrutinib BTK
Ibrutinib BTK Ibrutinib BTK Ibrutinib BTK Ibrutinib BTK Ibrutinib BTK
Acalabrutinib BTK Acalabrutinib BTK Acalabrutinib BTK Acalabrutinib BTK Acalabrutinib BTK Zanubrutinib BTK Zanubrutinib BTK Zanubrutinib BTK Zanubrutinib BTK Zanubrutinib BTK Zanubrutinib BTK Enzastaurin PKC Enzastaurin PKC Enzastaurin PKC Buparlisib PI3K Buparlisib PI3K Buparlisib PI3K Idelalisib PI3K Idelalisib PI3K Idelalisib PI3K Parsaclisib PI3K Parsaclisib PI3K Parsaclisib PI3K Everolimus mTOR
Everolimus mTOR Everolimus mTOR Temsirolimus mTOR
IMO-8400 TLR7/8/9
IMO-8400 TLR7/8/9
Overall response rate
33%
93% 83% 37% 5% 68-88%
Ongoing Ongoing Ongoing Ongoing Ongoing Ongoing Ongoing Ongoing Ongoing Ongoing Ongoing
11.5% 22.7% 25% 40% 47% 80% 30% 67% 78% 20-32%
70%
30% 32-47%
B-NHL
Relapsed ABC
WM PCNSL ABC-DLBCL GCB-DLBCL Relapsed MCL
CLL
MCL DLBCL ABC-DLBCL MCL
B-cell lymphoma Relapsed MCL Relapsed WM Relapsed CLL Relapsed MZL WM
MCL Relapsed DLBCL Relapsed WM Relapsed DLBCL Relapsed MCL PCNSL Relapsed MCL Relapsed MZL Relapsed LPL/WM Relapsed DLBCL Relapsed MCL Relapsed MZL Relapsed MCL
Relapsed WM Relapsed DLBCL Relapsed MCL
Relapsed DLBCL
Relapsed WM
N. of patients
Ref. of trial registration
12 (NCT01325701)
55 (NCT01614821) 6 120
38 (NCT01325701)
20 (NCT01325701)
16 (NCT02169180) 139 (NCT01646021) 111 (NCT01236391)
~306 (NCT02029443)
~124 (NCT02213926)
~39 (NCT03571308)
~21 (NCT02112526)
~70 (NCT02717624)
~44 (NCT03189524)
~86 (NCT03206970)
~40 (NCT03332173)
~91 (NCT03206918)
~65 (NCT03846427)
~210 (NCT03053440)
61 (NCT00088205)
55 (NCT00042666)
46 (NCT00718419)
26 (NCT01693614)
22 (NCT01693614)
4 (NCT02301364)
40 (NCT01090414)
15 (NCT01282424)
10 (NCT01282424)
23 (NCT02018861)
14 (NCT02018861)
9 (NCT02018861)
35 (NCT00516412)
19141
51 (NCT00436618) 47141
47 (NCT01180049) 141 (NCT01646021)
6 (NCT02252146)
5 (NCT02363439)
B-NHL: B-cell non-Hodgkin lymphomas; BTK: Bruton tyrosine kinase; PKC: protein kinase C; PI3K: phosphoinositide 3-kinase; mTOR: mammalian target of rapamycin; TLR: toll- like receptor;ABC:activated B-cell;DLBCL:diffuse large B-cell lymphoma;WM:Waldenström macroglobulinemia;PCNSL:primary DLBCL of the central nervous system;GCB:ger- minal center B-cell like; MCL: mantle cell lymphoma; CLL: chronic lymphocytic leukemia; MZL; marginal zone lymphoma; LPL; lymphoplasmacytic lymphoma.
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haematologica | 2019; 104(12)