8. Therapy of relapsed refractory DLBCL

Patients with relapsed/refractory disease have traditionally been treated with HDT/ASCR as per PARMA trial in the pre-rituximab era [82]. However, many chemotherapy regimen combinations with rituximab have since been shown to be active. For instance, R-ICE (rituximab, ifosfamide, carboplatin and etoposide) when given in out-patient setting has shown ORR of 71% with an estimated 1-year EFS rate and OS rate of 60 and 72%, respectively [83]. More recently lenalidomide monotherapy in a phase II trial in patients not eligible for transplant, showed improvement in RR, PFS and OS in non-GCB subtype DLBCL [84]. Brentuximab vedotin, a CD30-directed antibody-drug conjugate has shown ORR of 44% (CR17%) in a planned subset analysis in a phase II study [85]. Bruton's tyrosine kinase (BTK) inhibitor ibrutinib is proposed to be active in DLBCL and is being tried in combination with R-ICE in relapsed patients [86] (clinical trials.gov-NCT02955628).

#### 8.1. Novel therapies and future directions

Many novel targeted agents are under trial and have been reviewed elsewhere [5]. A brief description of novel immune and cellular therapies has been presented below and in Table 5. Some novel therapeutic strategies being tested in double-hit lymphoma include the BCL2 inhibitor, PI3K inhibitor and mTOR inhibitor. The INKa/ARF deletion cause genomic instability. Constitutive activation of NFkB is being targeted in several trials of proteasome inhibitors, immunomodulatory agents, and B cell receptor signaling pathway inhibitors.


against 86% in those who had symptoms [79]. However, imaging can also pick up changes early on when disease recurs. Although imaging can diagnose recurrence earlier, it has not been shown to alter the outcomes. The current work up and follow up recommendations for DLBCL

The rate of secondary CNS involvement is 3–5% but it is much higher with certain risk factors. Risk factors for CNS involvement include [80] elevated LDH, >1 extranodal site, involvement of testis, renal, breast, epidural space or adrenal gland, high CNS-IPI or MYC + BCL2/BCL6 gene rearrangement. Patients with 3 or more of these risk factors have a risk of CNS recurrence of as high as 25%. Prognosis is very poor with CNS recurrence and death is inevitable with median overall survival of 2–5 months. Hence patients at high risk of CNS recurrence should be considered for intrathecal chemotherapy with methotrexate or ara-C or high-dose IV methotrexate with leucovorin rescue. The intrathecal chemotherapy can be incorporated once in each cycle; alternatively, IV high-dose methotrexate can be given on Day 15 of 21-day R-CHOP. CNS prophylaxis has been

Patients with relapsed/refractory disease have traditionally been treated with HDT/ASCR as per PARMA trial in the pre-rituximab era [82]. However, many chemotherapy regimen combinations with rituximab have since been shown to be active. For instance, R-ICE (rituximab, ifosfamide, carboplatin and etoposide) when given in out-patient setting has shown ORR of 71% with an estimated 1-year EFS rate and OS rate of 60 and 72%, respectively [83]. More recently lenalidomide monotherapy in a phase II trial in patients not eligible for transplant, showed improvement in RR, PFS and OS in non-GCB subtype DLBCL [84]. Brentuximab vedotin, a CD30-directed antibody-drug conjugate has shown ORR of 44% (CR17%) in a planned subset analysis in a phase II study [85]. Bruton's tyrosine kinase (BTK) inhibitor ibrutinib is proposed to be active in DLBCL and is being tried in combination with R-ICE in

Many novel targeted agents are under trial and have been reviewed elsewhere [5]. A brief description of novel immune and cellular therapies has been presented below and in Table 5. Some novel therapeutic strategies being tested in double-hit lymphoma include the BCL2 inhibitor, PI3K inhibitor and mTOR inhibitor. The INKa/ARF deletion cause genomic instability. Constitutive activation of NFkB is being targeted in several trials of proteasome inhibitors, immunomodulatory agents, and B cell receptor signaling pathway

are summarized in Table 4.

58 Hematology - Latest Research and Clinical Advances

reviewed elsewhere in detail [81].

8. Therapy of relapsed refractory DLBCL

relapsed patients [86] (clinical trials.gov-NCT02955628).

8.1. Novel therapies and future directions

inhibitors.

7.8. CNS prophylaxis


8.2. CAR T cells

Enzastaurin [109]

Kinase inhibitors Fostamatinib [108]

Spleen oral tyrosine kinase (Syk) inhibitor

Protein kinase beta inhibitor

Chimeric antigen receptor (CAR) confers antigen specificity to T cells for antigens expressed by lymphoma cells in a non-MHC restricted fashion. The typical CAR T cell in clinical practice has an antigen binding pocket or single chain variable fragment (scFv) derived from an immunoglobulin molecule and a spacer or a hinge region and a range of different co-stimulatory molecules (CD 28, OX 40, 4-1BB). CD19 is expressed during all stages of B cell differentiation and is absent in any other cell types. Kochenderfer et al. reported the initial results on 15 patients with advanced B cell malignancies of which 8 achieved complete remissions (CR), 4 achieved partial remissions (PR) [87]. Some of the patients had a durable response. This led to the single arm, phase II JULIET study of CTL09 in adult patients with relapsed or refractory DLBCL. The overall response rate (ORR) was 45 with 37% achieved a complete response, and 80% achieving a partial response (PR), respectively [88]. This overall response rate was impressive in this heavily pretreated population. 57% of all treated patients experienced cytokine release syndrome (CRS) and 26% experienced grade 3, 4 CRS. The CAR T cell therapy received FDA breakthrough designation for treatment for relapsed refractory lymphoma in the United States based on the interim results of the JULIET trial. United States FDA finally approved axicabtagene ciloleucel for DLBCL following 2 prior therapies based on phase II Zuma-1 study [89] that showed 82% ORR and 54% CR rate. Development of the CAR T cells takes time and that becomes a limitation of this therapy in patients with rapidly progressive disease. Also cytokine release syndrome (CRS) and neurotoxicity (grade 3 or more CRS in Zuma-1 in 13% and neurotoxicity in 28% patients) can be life threatening and requires considerable expertise and critical care support which may be a limitation to the wide use of CAR T cells in

Drug MOA (target) Eligibility (and design) Phase Subjects (N) Results

For maintenance among high risk patients after CR to first line therapy

Table 5. Novel therapies undergoing clinical trials for the treatment of DLBCL.

Refractory/relapsed II 68 The most common

treatment-related adverse events of all patients were diarrhea (21% total, 6% grade 3/4), nausea (19% total, 3% grade 3/4), and, fatigue (18% total, 9% grade 3/4). The ORR rate was 3% across both arms and clinical benefit (≥stable disease) was achieved for 13% of all patients

61

Recent Advances in Diffuse Large B Cell Lymphoma http://dx.doi.org/10.5772/intechopen.74263

> hazard ratio for Enzastaurin vs. placebo was 70 vs. 71%, respectively

III 758 At 48 months, DFS


Table 5. Novel therapies undergoing clinical trials for the treatment of DLBCL.

#### 8.2. CAR T cells

Drug MOA (target) Eligibility (and design) Phase Subjects (N) Results

in DLBCL in untreated patients aged 60– 80 years

maintenance therapy vs. placebo in elderly patients with DLBCL who achieved a complete response (CR) or partial response (PR) to R-CHOP induction

Previously untreated non-GCB DLBCL (R-CHOP vs. VR-CHOP) thrombocytopenia in 84% and neutropenia in

including 17% CR with a DOR of 16.6 months

PFS was not reached for

and 18% with VR-CHOP. 2-year PFS rates were 77.6% with R-CHOP and 82.0% with VR-CHOP; ORR with R-CHOP and VR-CHOP was 98% and 96%, respectively. 2-year OS was 88.4 and 93.0%

14.5 months. MEF2B positive were significantly associated with response

responses, 1 CR at 31+

29% PR). 35% SD. DOR

months

18%)

not reached

lenalidomide maintenance vs. 58.9 months for placebo. At 52 months OS was similar between the two arms. Most common grade 3 or 4 adverse events associated with lenalidomide vs. placebo maintenance were neutropenia (56 vs. 22%) and cutaneous reactions (5 vs. 1%), respectively

79%

III 650 At 39 months median

II 206 PFS 25% with R-CHOP

Refractory/relapsed II 40 28% response. DOR

CTLA-4 inhibitor Refractory/relapsed I 18 2 patients had clinical

PD-L1 inhibitor PMBCL Ib 19 ORR 41% (12% CR and

Nivolumab [93] PD-1 inhibitor Refractory/relapsed I 11 ORRs 36% (CR, 18%; PR,

Refractory/relapsed II 49 DLBCL ORR 49% for DLBCL,

90Yepratuzumab tetraxetan [101]

Brentuximab vedotin (SGN-35) [102]

Lenalidomide [103]

Targeted therapies Bortezomib [104]

Panobinostat [105]

Ipilimumab [106]

Pembrolizumab

[107]

Immune checkpoint inhibitors

Immunomodulatory agents

Radiolabeled humanized anti-CD22 mAb

60 Hematology - Latest Research and Clinical Advances

Antitubulin monomethyl auristatin E (MMAE) anti-CD30 mAb conjugate

Proteasome inhibitor

Deacetylase inhibitor

Immunomodulator Lenalidomide as

Chimeric antigen receptor (CAR) confers antigen specificity to T cells for antigens expressed by lymphoma cells in a non-MHC restricted fashion. The typical CAR T cell in clinical practice has an antigen binding pocket or single chain variable fragment (scFv) derived from an immunoglobulin molecule and a spacer or a hinge region and a range of different co-stimulatory molecules (CD 28, OX 40, 4-1BB). CD19 is expressed during all stages of B cell differentiation and is absent in any other cell types. Kochenderfer et al. reported the initial results on 15 patients with advanced B cell malignancies of which 8 achieved complete remissions (CR), 4 achieved partial remissions (PR) [87]. Some of the patients had a durable response. This led to the single arm, phase II JULIET study of CTL09 in adult patients with relapsed or refractory DLBCL. The overall response rate (ORR) was 45 with 37% achieved a complete response, and 80% achieving a partial response (PR), respectively [88]. This overall response rate was impressive in this heavily pretreated population. 57% of all treated patients experienced cytokine release syndrome (CRS) and 26% experienced grade 3, 4 CRS. The CAR T cell therapy received FDA breakthrough designation for treatment for relapsed refractory lymphoma in the United States based on the interim results of the JULIET trial. United States FDA finally approved axicabtagene ciloleucel for DLBCL following 2 prior therapies based on phase II Zuma-1 study [89] that showed 82% ORR and 54% CR rate. Development of the CAR T cells takes time and that becomes a limitation of this therapy in patients with rapidly progressive disease. Also cytokine release syndrome (CRS) and neurotoxicity (grade 3 or more CRS in Zuma-1 in 13% and neurotoxicity in 28% patients) can be life threatening and requires considerable expertise and critical care support which may be a limitation to the wide use of CAR T cells in the community hospital setting [90]. The use of humanized anti IL-6 receptor antibody tocilizumab have been successfully used to manage these toxicities. Pretreating these patients with lymphotoxic agents such as cyclophosphamide or fludarabine is helpful for the survival of the infused T cells. Targeting of normal B cells results in B cell aplasia which may require intermittent infusion of immunoglobulin as prophylaxis from infectious complications. Upregulation of PD-1 expression has been shown among responders to CD19 CAR T cells. This may be vital in developing further strategies including combination therapies [91].

[2] Non-Hodgkin Lymphoma— Cancer Stat Facts. 2017. Available from: https://seer.cancer.

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[3] Leeksma OC, de Miranda NF, Veelken H. Germline mutations predisposing to diffuse

[4] Alizadeh AA, Elsen MB, Davis RE, Ma C. Distinct types of diffuse large B-cell lymphoma

[5] Sehn LH, Gascoyne RD. Diffuse large B-cell lymphoma: Optimizing outcome in the

[6] Scott DW, Mottok A, Ennishi D, Wright GW, Farinha P, Ben-Neriah S, et al. Prognostic significance of diffuse large B-cell lymphoma cell of origin determined by digital gene expression in formalin-fixed paraffin-embedded tissue biopsies. Journal of Clinical

[7] Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lym-

[8] Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;

[9] Adams J, Harris A, Pinkert C, Corcoran L, Alexander W, Cory S, et al. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in trans-

[10] Johnson NA, Slack GW, Savage KJ, Connors JM, Ben-Neriah S, Rogic S, et al. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. Journal of Clinical

[11] Green TM, Young KH, Visco C, Xu-Monette ZY, Orazi A, Go RS, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincris-

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1269-1277

## 8.3. Immune checkpoint inhibitors

Checkpoint proteins such as PD-1 on T cells and PD-L1 on tumor cells help keep immune responses in check. The binding of PD-L1 to PD 1 keeps T cells from killing tumor cells in the body. Blocking the binding of PD-L1 to PD-1 with an immune checkpoint inhibitor allows T cell to kill tumor cells. PD L-1 expression has been variable in different subsets of lymphomas. PD-L1 expression in follicular lymphomas is seen but the role in DLBCL is not that clear [92]. Lesokhin et al. did a phase 1b study of Nivolumab every 2 weeks in patients with relapsed refractory B cell, T cell, Multiple myeloma patients. 11 patients had DLBCL. ORR were 36% in the DLBCL patients [93]. Genetic alterations in 9p24.1 are known to upregulate PD-L1 and PD-L2 expression. This is seen in Hodgkin's lymphoma and also in patients with primary mediastinal B cell lymphoma. This was studied in a phase 1b trial of pembrolizumab in relapsed refractory primary mediastinal B cell lymphoma. ORR of 41% was seen among the 18 patients enrolled with 35% of patients had stable disease [94]. Patients with EBV-associated DLBCL and T cell rich B cell lymphomas express high levels of PD-L1 and warrant further studies with checkpoint inhibitors.
