Real-world efficacy and safety of Rituximab, Lenalidomide and İbrutinib combination in patients with Relapsed and/or Refractory Non-Hodgkin Lymphoma

doi:10.21203/rs.3.rs-3335343/v1

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Research Article

Real-world efficacy and safety of Rituximab, Lenalidomide and İbrutinib combination in patients with Relapsed and/or Refractory Non-Hodgkin Lymphoma

https://doi.org/10.21203/rs.3.rs-3335343/v1

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published 28 Nov, 2023

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Background

Relapsed or refractory (R/R) Non-Hodgkin Lymphoma (NHL) is associated with poor outcomes and the therapic options are limited. Recently, rituximab, lenalidomide, and ibrutinib (RLI) suggest promising efficacy in some clinical studies. Consequently, we evaluated the RLI in a real-life setting.

Methods

This retrospective, single-center study analyzed the outcomes of RLI as an off label salvage theraphy in patients with R/R NHL from June 2020-April 2022.

Results

We analyzed twenty-one patients including diffuse large B-cell lymphoma (DLBCL) (n = 16), primary central nervous system lymphoma (PCNSL) (n = 2), mantle cell lymphoma (MCL) (n = 2), marginal zone lymphoma (MZL) (n = 1). The most common adverse events (AEs) were fatigue (48%), neutropenia (48%), infection (33%). The median TTR (time to response) was 2 months (range, 1.7–3.8). The ORR (overall response rate) was 38% (95% CI 15%-61%) with 29% CR (complete response) and 9% PR (partial response). The median DoR (duration of response) was 12.8 months (range, 4.4–19.5+). The median OS (overall survival) was 7.9 months (95% CI 2.2–13.5) and median PFS (progression free survival) was 3.5 months (95% CI 0.0-8.3).

Conclusions

Our results suggest that RLI is a viable therapeutic option with promising activity and favorable toxicity profile in patients with R/R NHL.

Relapsed and/or refractory

NHL

rituximab

ibrutinib

lenalidomide

Relapsed and/or refractory (R/R) non-Hodgkin lymphoma (NHL) is associated with poor outcomes and the therapic options are limited particularly in patients who are ineligible for autologous stem cell transplantation (ASCT) because of their age or comorbidities and in patients who relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although chimeric antigen receptor T-cell therapies (CAR-T) have a remarkable success for long-term disease control, the need for novel treatments remain due to the inaccessibility of the treatment in most centers, the lack of response to treatment in some patients and the potentially limiting toxicity that causes intolerance in some patients.

Preclinical studies have demonstrated Bruton’s tyrosine kinase (BTK) inhibitör ibrutinib and lenalidomide showed synergistic activity when used in combination.¹ Ibrutinib disrupts B-cell receptor pathway via blocking BTK upstream and leading to decreased nuclear factor-_KB activity. Lenalidomide is an immunomodulatory drug that downregulates expression of interferon regulatory factor 4 and myeloid differentiation primary response 88 (MYD88) signaling. Ibrutinib and lenalidomide induce a lethal interferon production in malign cells through these mechanisms.¹ Rituximab, a chimeric monoclonal antibody that binds CD20 on B cells is used in most treatment regimens for B-cell NHL. However, many patients who initially respond to rituximab eventually develop rituximab resistance. Lenalidomide may also overcome rituximab resistance and its combination with rituximab results in durable responses in patients with NHL.²

Recently in some clinical trials, the triplet combination of rituximab, lenalidomide, and ibrutinib (RLI) demonstrated promising efficacy in patients with R/R NHL.^3,4 Consequently, we report outcome of patients with R/R NHL treated with RLI in this retrospective study aiming at evaluating efficacy and safety of RLI in a real life setting.

Twenty-one patients with R/R NHL who were treated with RLI as an off-label salvage therapy between June 2020 to April 2022 were analysed retrospectively. Relevant clinical datas were obtained by the review of medical records including age, gender, bone narrow involvement at diagnosis, prior therapies (included transplant ASCT and/or allo-HSCT, ibrutinib, lenalidomide) and presence of bulky disease. Diagnoses were pathologically confirmed in all patients and the cell of origin was determined by using the Hans algorithm in patients with Diffuse Large B-cell Lymphoma (DLBCL) and Primary Central Nervous System Lymphoma (PCNSL) [Germinal Center B-Cell–like (GCB), Activated B-cell (ABC), Not Otherwise Specified (NOS)].

In induction phase, all patients received lenalidomide 10, 15, 20 or 25 mg per os (po) daily on days 1 to 21 of each 28 day treatment cycle and ibrutinib 560 mg po daily on days 1 to 28. Patients with DLBCL, PCNSL and Marginal Zone Lymphoma (MZL) received 375 mg/m² intravenous (i.v) rituximab on day 1 of cycles 1 to 6 every 28 days, while patients with mantle cell lymphoma (MCL) received the same dose of rituximab once a week for 4 weeks during cycle 1, then every 8 weeks during 12 cycles. During the maintenance phase, ibrutinib and/or lenalidomide was administered po as per cohort dose daily until progression or occurrence of unacceptable toxicity (Fig. 1). We administrated HBV-suppressive therapy for patients with evidence of prior HBV infection, 100 mg/day of aspirin to all patients for venous thromboembolism prophylaxis while receiving lenalidomide and 300 mg/day allopurinol for tumor lysis prophylaxis with the initiation of therapy. Allopurinol was discontinued according to physician decision.

Computed tomography (CT) and/or positron emission tomography (PET) scans and bone marrow examination were performed before the first cycle. Disease responses to were assessed according to the Lugano criteria with restaging every 1–4 cycles thereafter, up to cycle 25. After cycle 25 CT and/or PET scans and bone marrow examination (when involved) were done every 6 months.⁵ Bone marrow biopsies were performed until confirmation of complete remission and were double-checked at sequential control cycle. Magnetic resonance imaging (MR) was used to evaluate CNS. The primary end point was the assessment of overall response rate (ORR).

Secondary endpoints were complete response (CR), partial response (PR) time to response (TTR) (time from the start of treatment to the first objective response observed for patients who achieved a CR or PR) duration of response (DoR) (time from date of response to date of disease progression or death), overall survival (OS), progression-free survival (PFS) and safety. Patients were evaluated for subsequent cancer therapies and OS after RLI discontinuation.

Safety was assessed with adverse events (AEs) monitoring and laboratory analyses. Hemogram and biochemical analysis were evaluated on every 7–10 days of each cycle. We administrated granulocyte colony-stimulating factors (g-csf) to patients who had grade 3–4 neutropenia. Dose modification (escalation and/or deescalation), delays, and discontinuations were recorded for specific AEs. Toxicity was summarized for the total number of patients, and each dose level. All AEs were graded according to Common Terminology Criteria for Adverse Events (version 4.0)

For statistical analysis demographics and patient characteristics were summarized by descriptive statistics. (continuous variables, median (minimum-maximum); categorical variables, frequency). The response analysis was done by intention to treat. OS and PFS were estimated by using the Kaplan-Meier method. All statistical analyses were done with SPSS v.20. This study was approved by local ethics board (10.12.2021; İ10-664-21).

Twenty-one patients with DLBCL (n = 16), PCNSL (n = 2), MCL (n = 2), and MZL (n = 1) were included in this retrospective study. Lenalidomide was given at adose of 25 mg (n = 9), 15 mg (n = 11) and 10 mg (n = 1 ) respectively. The baseline demographic and clinical characteristics of patients before initiation of RLI are summarized in Table 1. Median age of patients at study entry was 60 years (range, 24–84). Eleven patients (52%) were older than 60 years. Median time between the diagnosis and the initiation of RLI was 2.3 years (range, 0.4–27.5 years). Eleven (53%) patients had advanced stage disease. Among 18 patients with DLBCL and PCNSL, the ABC type (n = 7) and NOS type (n = 5) were more frequent than GCB type (n = 4). Nine of 16 patients (56%) with DLBCL had MYC and BCL2 and/or BCL6 rearrangements.

All patients were heavily pretreated with a median number of prior chemotherapy lines of 3 (range, 2–6). Eleven patients (53%) had prior ASCT and 2 underwent allo-HSCT. Six patients received ibrutinib and/or lenalidomide before RLI (n = 2 ibrutinib monotherapy, n = 2 lenalidomide monotherapy, n = 2 lenalidomide plus ibrutinib). The most common prior therapies were respectively R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) (81%), R-DHAP (29%) (rituximab, dexamethasone, cytarabine, cisplatin), ibrutinib and/or lenalidomide (29%). Disease status prior to the initiation of RLI showed that 12 (57%) patients had disease refractory to prior treatment, including 7 (33%) of patients who had primary refractory disease. Among the remaining 9 (43%) patients with relapsed disease, one patient relapsed within 12 months after the first line treatment, whereas five patients relapsed more than 24 months. Eight (38%) patients had bulky disease (≥ 5 cm) before RLI theraphy. The tumor size was ≥ 10 cm in 4 patients.

Median follow-up time was 6.6 months (range, 0.4–22.3 months). Median duration of RLI treatment was 2.9 months (range, 0.4–21.2 months). Eleven patients (52%), 6 patients (29%) and 2 patients (10%) received RLI treatment for more than 3, 6 and 12 months, respectively. Three patients (14%) were receiving ibrutinib and/or lenalidomide as a maintenance therapy at the time of the analysis. Patients had received a median of 3 (range, 1–19) cycles of RLI treatment. Six (29%) patients (3 DLBCL, 2 MCL, 1 MZL) completed the induction phase which included 6 rituximab doses. RLI treatment was discontinued RLI in 15 patients due to disease progression 53% (8/15), disease relapse 7% (1/15), the end of RLI treatment 33% (5/15) and infection 7% (1/15).

All of the patients were evaluable for response. The median time to response was 2 (range, 1.7–3.8) months. The ORR was 38% (95% confidence interval [CI]: 15%-61%; n = 8) including 29% (n = 6) CR and 9% (n = 2) PR (Fig. 2). The disease control rate (DCR) [CR + PR + SD] was 67% (95% CI:45%-89%; n = 14) including with 29% (n = 6) stable disease (SD). At the time of the analysis, the median DoR was 12.8 months (range, 4.4–19.5+).

Responses were more common in patients with ABC (n = 7; ORR 43%, including all with CR) and MYC and BCL2 and/or BCL6 rearrangements (n = 9; ORR 33.3%, including all with CR), compared with GCB DLBCL (n = 4; ORR 25%, including all with CR) (Fig. 3). The median DoR with DLBCL and PCNSL patients was 15.5 months (range, 4.4–19.5+), 16.4 months for patients with non-GCB disease (n = 3 ABC; n = 2 NOS) and 4.7 months for patients with GCB disease (n = 1). Seven of 8 (88%) patients with CR and PR had relapsed disease before RLI Among 8 patients with bulky disease, only 1 (12.5%) patient achieved CR, [1 PR (12.5%), 3 SD (37.5%) and 3 PD (37.5%)].

Among patients with CR (n = 6), all but one had relapsed disease before RLI and non-GCB subtype. Half of the patients received ASCT prior to RLI treatment. RLI cycles were followed by ASCT (n = 1), allo-HSCT (n = 1), standard chemotherapy (n = 2) and lenalidomide plus ibrutinib maintenance (n = 1). These patients maintained their CR at the time of analysis. One patient relapsed while on maintenance treatment with lenalidomide plus ibrutinib. The DoR was ≥ 1 year at the time of analysis in 4 patients with CR (Table 2).

Deaths had occured in 13 (62%) patients. Ten were due to PD and 3 deaths were AE related due to Covıd-19 pneumonia, sepsis and pancytopenia. Four patients with PD who has stage 4 DLBCL before initiation of treatment died within 30 days of RLI treatment. The patient was a 56-year-old woman, had recieved 5 prior lines of theraphy including ASCT and allo-HSCT. This patient developed CNS relapse and received RLI treatment for 13 days. The patient was a 71-year-old man who received treatment for 22 days before a temporary interruption for difficulty in swallowing and worsening of patient’s condition, with death occurring 3 days after treatment discontinuation. The patient was a 60-year-old woman, discontinued of RLI on 24th day, within 8 days before death. The patient was a 24-year-old woman had a primary refractory bulky disease (11×12 cm mass in the midline of the pelvis) who received RLI for 23 days, in the following days developed grade 2 maculopapular rash, klebsiella oxytoca pneumonia, with death occurring 12 days after RLI treatment discontinuation.

Median PFS and OS were 3.5 months (95% CI 0.0-8.3 months) and 7.9 months (95% CI 2.2–13.5 months). The 3-month PFS was %38 (95% CI 8–69) and the 3-month OS was 43% (95% CI 13–73). Survival was significantly higher among responders compared to nonresponders (OS median not estimable (NE) versus 2.8 months; mean 19.7 versus 4.7 months, log-rank p < 0.05; PFS median NE versus 1.8 months; mean 19.6 versus 3.7 months, log-rank p < 0.05) (Fig. 4). Among patients with DLBCL/PCNSL median OS was 4 months (95% CI 1.5–6.4 months) and median PFS was 3 months (95% CI 1.6–4.4 months) which did not differ according to subtype of disease. Although patients with ABC type showed a tendency toward better OS than patients with GCB and NOS&NA type. OS and PFS were not influenced by MYC and BCL2 and/or BCL6 rearrangements (Fig. 4).

The patient had stage 4, relaps disease was 62-year-old man who received 3 cycles of RLI with PD response. The patient received four cycles of glofitamab, but the size of the lesion progressed. He received T(R)EC (rituximab, ifosfomide, carboplatin, etoposide) regimen as salvage theraphy, but ultimately died after the first cycle due to covid-19 infection. The patient had stage 4, primary refractory, bulky disease (22 x 15 cm mass in the mediastinum) was a 42-year-old woman who received RLI alone in cycle 1 lead in followed by RLI combined with standard chemotherapy (bendamustine) and radiotherapy for 1 cycle with SD response. She received two cycles of glofitamab, but died because of progressive disease and sepsis. The unresponsive patient had stage 1 relapsed refractory MZL was a 84-year-old woman who received 19 cycles of RLI with SD response. She received one cycle of PEP-C (prednisone, etoposide, procarbazine and cyclophosphamide) with response assessment nonapplicable (N/A). The patient had stage 1 relapsed PCNSL was 47-year-old man who received 5 cycles of RLI with CR response. After relapse he received one cycle of temozolomide, etoposide, doxil, dexamethasone, and rituximab (TEDDI-R) with no response. The patient died due disease progression.

Treatment-emergent adverse events (AEs) are summarized in Table 3. A total of seven patients (33%) experienced a grade 3 or 4 nonhematologic toxicity. The most common nonhematologic AEs of any grades were fatigue (48%), infection (38%) and diarrhea (29%). The most frequently reported nonhematologic AEs were occurring at the 25 mg L dose (63%), but the majority (77%) of patients experienced a grade 1–2 AE. There were no incidences of bleeding, thrombosis, or secondary malignancy. Three patients (14%) experienced atrial fibrillation and none of them discontinued the treatment. Two patients (10%) developed a maculopapular rash. Grade 3–4 rash occured in 1 patient with concurrent grade 3–4 neutropenia, thrombocytopenia and infection in cycle 3, and required treatment delay for a week. Discontinuation of the treatment resulted in complete resolution of the rash. The most common grade 3–4 hematologic AEs were neutropenia (48%) and thrombocytopenia (19%).

Four patients (19%) required dose reduction because of AEs [hypotension, fatigue (n = 1, 5%, 15 mg lenalidomide dose); febrile neutropenia (n = 1, 5%, ibrutinib); neutropenia, thrombocytopenia (n = 1, 5%, 25 mg lenalidomide dose and ibrutinib)] (Table 4). Twelve patients (57%) discontinued therapy because of AEs including infection (n = 2, 10%), grade 3–4 diarrhea (n = 2, 10%), grade 3–4 hypotension (n = 1, 5%), grade 3–4 neutropenia, thrombocytopenia (n = 4, 19%), disease progression (n = 2, 10%) and increase in the liver function tests (n = 1, 5%) (Table 5).

To our knowledge, this is the first real-world, single center data evaluating the efficacy and safety of combination treatment with rituximab, lenalidomide, and ibrutinib in patients with R/R NHL. Notwithstanding the poor prognostic features of study patients, including primary refractoriness (33%), advanced stage (53%) and bulky disease (38%), the analysis of clinical response shows the promising activity of RLI as well as its favorable toxicity profile. In the current study, ORR was 38% including 29% CR which is comparable to that of a previous multicenter phase 1b/2 study reporting ORR and CR rates of 38% and 24%, respectively in 45 patients with relapsed or refractory DLBCL.³ Goy and colleagues demonstrated greater activity of RLI in non-GCB DLBCL with a median duration of response of 15.9 months.³ In our study, patients with CR or PR were higher in non-GCB type but survival outcomes did not differ between subtypes due to small number of responders. Similarly, median DOR was longer in patients with non-GCB than GCB DLBCL (16.4 vs 4.7 months, respectively).

Optimal dose of lenalidomide in RLI combination for R/R NHL patients remains unclear. Promising activity of RLI combination was observed with doses at least 15 mg lenalidomide in adults with relapsed/refractory DLBCL in phase 1b study.³ In a phase 2 trial (PHILEMON) reported by Jerkeman, the ORR was 76% with 56% CR with RLI combination at a dose of 5–15 mg lenalidomide).⁴ A recent phase 1b/2 study evaluating efficacy of RLI in patients with R/R DLBCL ineligible for tem cell transplantation has shown that ORR was 53% and 44% in lenalidomide 20 mg and 25 mg cohorts respectively.⁶ Although the small number of patients in 10 mg lenalidomide cohort in our study, encouraging activity was observed at the 10 mg, 15 mg and 25 mg lenalidomide doses.

Promising activity of RLI in patients with R/R NHL led to initiation of studies in the first-line setting. The MD Anderson Cancer Center conducted Smart Start study aiming at evaluating efficacy of RLI in patients with newly diagnosed with DLBCL.⁷ In this Phase 2 trial, the CR and 2-year PFS rate was 94.5% and 91.3% after two cycles of RLI and than six additional cycles of conventional therapy combined with RLI. Based on these results, a Chinese real-world study was designed to evaluate the efficacy, safety of RLI and RLI followed by chemotherapy in de novo, unfit, elderly DLBCL patients.⁸ The ORR rates of the two groups were 87.5% and 92.3%, respectively. In a phase 2 study, RLI containing relatively higher dose but shorter duration of lenalidomide (25 mg daily for 10 days) was used for the treatment of frail or unfit 30 patients aged 75 years or older with de novo DLBCL. ORR was of 66.7% with CR rate of 56.7% and a 2-year OS, PFS were 66.7% and 53.3%, respectively.⁹ Although, only 4 R/R NHL patients were older than 70 years, 2 of them had response to RLI combination in our study.

Neutropenia which was observed with an incidence of 48% was the most frequent grade 3–4 AEs and was slightly more common than previousy reported in the literature.^3,4,6 Neutropenia was manageable with growth factors and only one patient had died because of grade 4 pancytopenia and sepsis. In a recent phase 1b/2 study, major haemorrhage was observed in 8% of patients partly due to advanced age and high rate of comorbidities.⁶ In our study, bleeding was not observed despite grade 3–4 thrombocytopenia with a frequency of 19%. Grade 3–4 non-haematological toxicities, including rush and atrial fibrillation were overall less of a concern and were well controlled in our patients. This may indicate that more heavily pretreated patients in our study.

Our study had several limitations. Relatively small number of sample size limits its statistical power. Its retrospective design, inclusion of patients with different types of lymphoma and the short follow-up time are other limitations of study.

In conclusion, despite its limitations, our results suggest that rituximab, lenalidomide, and ibrutinib combination is a viable therapeutic option for R/R NHL. The response rates to RLI were high although majority of the patients were difficult to manage due to older age, advanced stage disease, non-GCB subtype DLBCL/PCNLS, history of prior ASCT and several lines of therapy. During the treatment, short follow-up intervals and intermittent G-CSF support could reduce AEs. Further prospective studies with long term follow up are required to support our results.

Ethical approval : All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Conflict of Interest: None of the authors have a conflict of interest to disclose.

Authors' contributions :

Surgical and Medical Practices DERYA KOYUN, UĞUR ŞAHİN, AYLA GÖKMEN, MUHİT ÖZCAN

Concept DERYA KOYUN, AYLA GÖKMEN, UĞUR ŞAHİN, MUHİT ÖZCAN

Design DERYA KOYUN, AYLA GÖKMEN, UĞUR ŞAHİN, MUHİT ÖZCAN

Data Collection or Processing DERYA KOYUN, UĞUR ŞAHİN, AYLA GÖKMEN, MUHİT ÖZCAN

Analysis or Interpretation DERYA KOYUN, UĞUR ŞAHİN, AYLA GÖKMEN, MUHİT ÖZCAN

Literature Search DERYA KOYUN, AYLA GÖKMEN, MUHİT ÖZCAN

Writing DERYA KOYUN, AYLA GÖKMEN, MUHİT ÖZCAN

Funding: This study has no funding.

Availability of data and materials: Not applicable

Yang Y, Shaffer AL III, Emre NC, et al. Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma. Cancer Cell. 2012;21(6):723-737.
Chong EA, Ahmadi T, Aqui NA, et al. Combination of lenalidomide and rituximab overcomes rituximab resistance in patients with indolent B-cell and mantle cell lymphomas. Clin Cancer Res. 2015;21(8):1835-18.
Goy A, Ramchandren R, Ghosh N, et al. Ibrutinib plus lenalidomide and rituximab has promising activity in relapsed/refractory nongerminal center B-cell DLBCL. Blood. 2019;134(13):1024-1036.
Mats Jerkeman, Christian Winther Eskelund, Martin Hutchings, et al. Ibrutinib, lenalidomide, and rituximab in relapsed or refractory mantle cell lymphoma (PHILEMON): a multicentre, open-label, single-arm, phase 2 trial. Lancet Haematol 2018; 5: 109–16.
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 2014; 32: 3059–68.
Ramchandren R, Johnson P, Ghosh N, et al. The iR2 regimen (ibrutinib plus lenalidomide and rituximab) for relapsed/refractory DLBCL: A multicentre, non-randomised, open-label phase 2 study. EClinicalMedicine 2022; 56: 101779.
Westin J, Davis RE, Feng L, et al. Smart Start: Rituximab, Lenalidomide, and Ibrutinib in Patients With Newly Diagnosed Large B-Cell Lymphoma. J Clin Oncol. Published online August 11, 2022: JCO2200597.
Zhu Y, Zhang X, Wei J. Rituximab, lenalidomide and BTK inhibitor as frontline treatment for elderly or unft patients with difuse large B-cell lymphoma: a real-world analysis of single center. Experimental Hematology & Oncology (2022) 11:57.
Xu P-P, Shi Z-Y, Qian Y, et al. Ibrutinib, rituximab, and lenalidomide in unfit or frail patients aged 75 years or older with de novo diffuse large B-cell lymphoma: a phase 2, single-arm study. Lancet Healthy Longev 2022; 3: e481–90.

Table 1. Characteristics of Patients Prior to RLI

Sex, n (%)	Male	10 (48)
Sex, n (%)	Female	11 (52)
Age, median (min-max)		60 (24-84)
NHL subtype	DLBCL	16 (76)
	MCL	2 (9.5)
	PCNSL	2 (9.5)
	MZL	1 (5)
Stage at diagnosis, n (%)	Stage 1	7 (33)
	Stage 4	11 (53)
	Unknown	3 (14)
Previous treatment lines before RLI	2	8 (38)
	3	8 (38)
	4	2 (9.5)
	5	2 (9.5)
	6	1 (5)
Bulky Disease before RLI		8 (38)
SCT, Ibrutinib, Lenalidomide therapies before RLI	ASCT	11 (53)
	ASCT+Allo-HCST	2 (9.5)
	Ibrutinib	3 (14)
	Lenalidomide	3 (14)
Bone narrow involvement at diagnosis		4 (19)
DLBCL/PCNSL subtype	GCB	4 (22)
	ABC	7 (39)
	NOS	5 (28)
	N/A	2 (11)
Disease status before RLI	Primary Refractory	7 (33)
	Relapsed	9 (43)
	Relapsed/ Refractory	5 (24)
Median time between the last theraphy and RLI, day (min-max)		56 (0-1731)

ABC: Activated B-cell, allo-HSCT: allogeneic hematopoietic stem cell transplantation, ASCT: autologous stem cell transplantation GCB: Germinal Center B-Cell–like, min:minumum, max:maximum, N/A: Non-applicable, NOS: Not Otherwise Specified.

Table 2. Characteristics of Patients with CR

PATIENT (P)	The reasons for RLI discontinuation	Treatment after RLI	Disease status after RLI	DoR (day)
1	The End of Treatment	3XR-CHOP+3 RLI	CR	494
2	The End of Treatment	2XR-miniCHOP	CR	585
3	The End of Treatment	allo-HSCT	CR	441
4	The End of Treatment	ASCT	CR	576
5	Continued	Lenalidomide plus Ibrutinib	CR	141
6	Disease Relapse	TEDDI-R	relapse	133

P	AGE	SEX	STAGE	subtype	dIagnosIs	LINES OF THERAPHY before RLI	ASCT	Allo-HCST	Bulky DIsease before RLI	DIsease status before RLI	RLI cycle
1	67	F	N/A	ABC	DLBCL	2	+	-	-	RELAPS	9
2	71	M	1	ABC	DLBCL	2	-	-	-	RELAPS	6
3	53	F	1	NOS	DLBCL	3	+	-	-	RELAPS	4
4	36	M	1	NOS	DLBCL	2	-	-	+ (5-10 cm)	RELAPS	3
5	66	F	4	GCB	DLBCL	3	-	-	-	Primary Refractory	6
6	47	M	1	ABC	PCNSL	2	+	-	-	RELAPS	5

F: Female, M: Male, R-CHOP: Rituximab,cyclophosphamide, doxorubicin, vincristine, prednisone, TEDDI-R: Temozolomide, etoposide, doxil, dexamethasone, and rituximab

Table 3. Treatment-emergent adverse events

Nonhematologic aEs	ALL GRADES	GRADE 1-2	GRADE 3-4	LEN 10 mg	LEN 15 mg	LEN 25 mg
Fatigue	10 (48%)	8 (38%)	2 (10%)	1 (10%)	2 (20%)	7 (70%)
Infection	8 (38%)	5 (24%)	3 (14%)	-	3 (37%)	5 (63%)
Diarrhea	6 (29%)	4 (19%)	2 (10%)	1 (17%)	3 (50%)	2 (33%)
Oral aphthae and Mucositis	4 (19%)	4 (19%)	1 (5%)	-	-	4 (100%)
Atrial fibrillation	3 (14%)	3 (14%)	-	-	2 (67%)	1 (33%)
Rash	2 (10%)	1 (5%)	1 (5%)	-	1 (50%)	1 (50%)
Hypotension	1 (5%)	-	1 (5%)	-	1 (100%)
Hypertensive crisis	1 (5%)	-	1 (5%)	-	-	1 (100%)
Liver function tests increased	1 (5%)	1 (5%)	-	-	-	1 (100%)
Vertigo	1 (5%)	1 (5%)	-	-	1 (100%)
Ecchymose	1 (5%)	1 (5%)	-	-	-	1 (100%)
Dyspnea	1 (5%)	1 (5%)	-	-	1 (100%)
Peripheral Edema	1 (5%)	1 (5%)	-	-	-	1 (100%)
Hypomagnesemia	1 (5%)	1 (5%)	-	-	-	1 (100%)
Cramp	1 (5%)	1 (5%)	-	-	-	1 (100%)
Nausea	1 (5%)	1 (5%)	-	-	-	1 (100%)
hematologic aEs
Neutropenia	10 (48%)	-	10 (48%)	-	4 (40%)	6 (40%)
Thrombocytopenia	4 (19%)	-	4 (19%)	-	2 (50%)	2 (50%)
Anaemia	4 (19%)	3 (14%)	1 (5%)	-	3 (14%)	1 (5%)

Table 4. Dose delays and/or reductions resulting from AEs

Starting Dose

LEN 15 mg

LEN 25 mg

Reason for dose reduction

n=1 10 mg; Hypotension, fatigue

n=1 15 mg; Grade 4 neutropenia, thrombocytopenia

Reason for dose delay

n=4

n=2 (50%) Infection

n=1 (25%) Grade 1-2 diarrhea

n=1 (25%) Hypotension, fatigue

n=7

n=3 (43%) Grade 4 neutropenia, thrombocytopenia

n=2 (29%) Disease progression

n=1 (14%) Increase in the liver function tests

n=1 (14%) Grade 3-4 diarrhea

Table 5. Reason for lenalidomide dose delays and/or reductions

	LEN 10 mg	LEN 15 mg	LEN 25 mg	All Doses
Dose delays and/or reductions resulting from AEs	-	4 (19%)	9 (43%)	13 (62%)
Dose reduction	-	1 (5%)	2 (10%)	3 (14%)
Lenalidomide	-	1 (5%)	1 (5%)	2 (10%)
Ibrutinib	-	-	2 (10%)	2 (10%)
Dose delay	-	4 (19%)	9 (43%)	13 (62%)
Lenalidomide	-	4 (19%)	7 (33%)	11 (52%)
Ibrutinib	-	3 (14%)	9 (43%)	12 (52%)

No competing interests reported.

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Journal Publication

published 28 Nov, 2023

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Real-world efficacy and safety of Rituximab, Lenalidomide and İbrutinib combination in patients with Relapsed and/or Refractory Non-Hodgkin Lymphoma

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