Treatment with Temozolomide and Ibrutinib in Recurrent/Refractory Primary (PCNSL) and Secondary CNS Lymphoma (SCNSL)

I ntroduction Despite recent therapeutic progress in this field, the prognosis of elderly patients with Primary (PCNSL) and Secondary Central Nervous System Lymphoma (SCNSL) remains poor, with a median OS of less than two years in most prospective studies. Patients with chemo refractory relapsed PCNSL within the first year from diagnosis have a median OS of 2-4 months. Activated B cell like subtype of Diffuse Large B Cell Lymphoma (DLBCL) and PCNSL relies on a chronically active B-cell receptor (BCR) signaling. Ibrutinib achieves CNS penetrance and has a high overall response rate in CNS lymphomas, but duration of response is short and curative potential is limited. A novel regimen that combines ibrutinib with temozolomide, etoposide, liposomal doxycycline, dexamethasone, and rituximab (Teddi-R) seems to be promising for this population but its tolerance is an issue in patients with advanced age and poor general condition, common features of many PCNSL patients., calling for an alleviated regimen of broader use. Patients and methods We evaluated a combination of temozolomide and ibrutinib in immunocompetent adult with recurrent/refractory (PCNSL) and (SCNSL) treated in five French centers between June 2015 and January 2020. The treatment consisted of 560 mg ibrutinib orally once daily (28-day cycles) and temozolomide 100 mg/m2 or 150 mg/m2 orally day 1 to 5 for cycle 1, increased to 200mg/m2 day 1 to 5 from cycle 2, until disease progression or unacceptable toxicity occurred. The evaluations were performed using Magnetic resonance imaging (MRI) and the responses were assessed according to the International PCNSL Collaborative Group Response Criteria. The lymphoma diagnoses were all confirmed by expert pathologists in the framework of the national program "lymphopath", based on the criteria of the World Health Organization 2008 classification. Results 22 immunocompetent adults with recurrent/refractory (PCNSL n=13) and (SCNSL n=9) were evaluable for safety and efficacy. Median age was 71 years (range, 44 - 89 years). All patients had relapsed (n=6) or refractory (n=16) disease, after a median of two lines of therapy (range, 1-3). Overall, 18 patients (82%) and 14 (64%) patients had previously received high dose methotrexate or both high dose methotrexate with high dose cytarabine, respectively. Among the four patients who did not receive Methotrexate, one had a chronic kidney disease secondary to diabetic nephropathy and experienced major toxicity after cytarabine infusion. The three others (72, 79 and 89 years old) were SCNSL experiencing comorbidities and toxicities from their previous treatment lines. Ten patients had a poor performance status according to Eastern Cooperative Oncology Group [ECOG] ⩾ 2. Patients received a median of 3.2 cycles (1-19 cycles). One patient received whole brain radiotherapy consolidation after obtaining a partial response under treatment. Best overall response rate was 55% (12/22) including 3 (13.6%) complete responses and 9 (40.9%) partial responses. After a median follow-up of 18.2 months (range, 5.1 - 61.7), the median progression-free survival was 5.3 months (95% confidence interval [CI]; 3.10 - NA) and overall survival 8.9 months (95% CI; 5.2 - NA). Eight patients (36%) received temozolomide and ibrutinib for more than 6 months, four patients were still on treatment at the end of the follow-up including one on ibrutinib only. Twelve patients (55%) stopped treatment due to progressive disease. Three (14%) patients stopped treatment for toxicity: Two (9%) due to grade 2 atrial fibrillation and one patient after 18 months in RC due to grade 1 muscle cramps, which did not stop after treatment discontinuation. three (14%) patients stopped temozolomide only due to recurrent grade 2 microcrystalline arthritis, grade 3 fall and one patient after 15 months in RC due to recurrent grade 2 bronchial infection, asthenia and nausea. Two patients temporary stopped treatment for grade 1 tumor hemorrhage and grade 3 tumor hemorrhage with grade 3 seizure. Micro-bleedings were seen at the MRI in four patients. Four patients (18%) experienced serious infectious complications including: two grade 3 febrile neutropenia, one grade 3 urinary tract infection and one grade 3 sepsis. None of the patients developed aspergillosis during the follow-up. Conclusion Temozolomide combined with ibrutinib showed clinical activity with manageable side effects in R/R CNS lymphomas. Disclosures Morschhauser: Novartis: Honoraria; JANSSEN-CILAG: Honoraria; Pharmacyclics LLC: Honoraria; Gilead: Honoraria; Roche: Honoraria; Celgene: Honoraria; Abbvie: Honoraria; Servier: Honoraria.

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Phase II Trial of Lenalidomide - Dexamethasone - Rituximab in Relapsed or Refractory Indolent B-Cell or Mantle Cell Lymphomas Resistant to Rituximab.

Blood ◽

10.1182/blood.v114.22.1700.1700 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1700-1700

Author(s):

Tahamtan Ahmadi ◽

Elise A. Chong ◽

Amanda Gordon ◽

Nicole A. Aqui ◽

Lisa H. Downs ◽

...

Keyword(s):

Follicular Lymphoma ◽

B Cell ◽

Disease Progression ◽

Phase Ii ◽

Overall Response Rate ◽

Response Rate ◽

Overall Response ◽

Mantle Cell ◽

Grade 3

Abstract Abstract 1700 Poster Board I-726 Introduction Lenalidomide is an immunomodulatory drug with effects on the innate immune system that may enhance antibody-dependent cell mediated cytotoxicity as well as the development of specific anti-tumor immune responses. These immunologic effects may synergize with the action of rituximab. To test the efficacy of lenalidomide combined with rituximab, we are conducting a single center, open label phase II clinical trial in patients (pts) with indolent B-cell or mantle cell lymphomas previously resistant to rituximab. Patients and Methods Eligible pts must have relapsed/refractory indolent B-cell or mantle cell lymphoma with measurable disease that has failed to respond to or has progressed within six months of a standard course of rituximab monotherapy (375 mg/m2 weekly for at least four weeks) or a prior rituximab-containing chemotherapy regimen. Thus, all pts enrolled are considered rituximab-resistant. In Part I (lenalidomide + dexamethasone), pts receive two 28-day treatment cycles of lenalidomide 10 mg every day and dexamethasone 8 mg once weekly. After assessment of response to Part I, all pts receive a single course of rituximab 375 mg/m2, consisting of four weekly doses during cycle 3 (Part II: lenalidomide + dexamethasone + rituximab). Treatment with lenalidomide + dexamethasone continue during and subsequent to rituximab; stable and responding pts continue on lenalidomide + dexamethasone until disease progression or development of clinically unacceptable toxicity. Response assessment after Part II is performed three months after the first dose of rituximab. Results To date, 22 pts have started therapy; diagnoses included: follicular (n = 17), mantle cell (n = 2), small lymphocytic (n = 2), and marginal zone (n = 1) lymphomas; median age was 59 years (range: 35 - 72); male: female ratio was 5:6; median number of prior therapies was 3 (range: 1 - 7); LDH was increased in 23%. For 21 pts with at least one follow-up visit, there were 2 deaths and 2 episodes of disease progression. One death due to myocarditis occurred during Part I treatment; one death due to lymphoma occurred in a patient removed from study due to grade 3 rash, which subsequently resolved. Both episodes of disease progression occurred in pts with follicular lymphoma, one of whom had been removed from study during Part 1 because of thrombocytopenia attributed to myelodysplasia. For all patients, at a median follow-up of 5.0 months (range: 0.3 - 12.3), progression-free survival (PFS) is 81% (95% CI: 51-94). For 10 pts with response assessments after Parts I and II, overall response rate (ORR) after Part I was 30% (3 CR; 6 SD; 1 PD) and ORR after Part II was 70% (5 CR; 2 PR; 2 SD; 1 PD). At a median follow-up of 7.8 months (range: 5.0 - 11.9), PFS is 89% (95% CI: 43-98) for these 10 pts. For pts who completed Parts I and II, grade 3 or 4 non-hematologic toxicities included hypokalemia (2/10 pts), hypophosphatemia (1/10 pts), and hypocalcemia (1/10 pts); grade 1 tumor flare occurred in one pt with follicular lymphoma. Conclusions Based on these preliminary data in rituximab-resistant patients with indolent B-cell or mantle cell lymphomas, the combination of continuous daily lenalidomide, low-dose weekly dexamethasone, and a single four week course of rituximab during cycle 3, achieves a high overall response rate with relatively durable responses. Additional follow-up and correlative studies will be presented. Disclosures Off Label Use: Lenalidomide is used in this trial for treatment of lymphoma.. Downs:Genentech: Honoraria; Celgene: Honoraria. Nasta:Genentech: Speakers Bureau. Schuster:Celgene: Consultancy, Research Funding.

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Survival Benefits of Patients with Non-Hodgkin’s Lymphoma Treated with Rituximab Combined with Chemotherapy.

Blood ◽

10.1182/blood.v104.11.4625.4625 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4625-4625

Author(s):

Zhixiang Shen ◽

Junmin Li ◽

Aihua Wang ◽

Yu Chen

Keyword(s):

B Cell ◽

Overall Response Rate ◽

Response Rate ◽

Cell Lymphoma ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Free Survival ◽

Overall Response ◽

Large B Cell

Abstract Purpose: Rituximab combined with chemotherapy has been recommended as first-line or second-line standard regimen in most subtypes of B-cell lymphoma in China by the 2004 National Comprehensive Cancer Network lymphoma therapy guideline. We have conducted a multicenter trial to evaluate the efficacy and safety of rituximab in combination with standard chemotherapy (CHOP) in patients with previously untreated or relapsed indolent and aggressive NHL. Methods: Patients received 4–8 cycles of rituximab plus CHOP every 21 days. For each cycle, rituximab (375mg/m2) was given on day 1 and CHOP started on day 3. CHOP consisted of cyclophosphamide 750mg/m2, doxorubicin 50mg/m2, and vincristine 1.4mg/m2 (maximum 2mg/dose) given intravenously on day 3, and oral prednisone 100mg on days 3–7. Results: A total of 221 patients were enrolled on the trial, 128 males and 93 females with a mean age of 49 years (range 10–83 years). The main lymphoma subtypes were small lymphocytic (15 patients, 7%), follicular (27 patients, 12%), and diffuse large B-cell (160 patients, 72%). In total, 56 patients had indolent NHL and 165 aggressive NHL. The overall response rate for all patients was 86% with 57% complete responses. In patients with indolent NHL the overall and complete response rates were 95% and 55% respectively. After a median 12 months follow up, progression-free survival in patients with indolent NHL was 88%±5% at 1 year and 83%±6% at 2 years. In the 160 patients with diffuse large B-cell lymphoma, the overall response rate was 88% with 61% complete responses, and after a mean follow-up of 6 months, predicted 1-year and 2-year progression-free survival were 88%±5% and 83%±7% respectively. Infusion-related adverse events occurred in 4% of patients, associated with the first infusion of rituximab. Subanalyses according to subtype, stage, IPI and other factors will be presented. Conclusion: Rituximab plus chemotherapy is an effective, well-tolerated treatment that achieves high response rates and long progression-free survival in both indolent and aggressive NHL.

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Rituximab Increases Response to ESHAP in Relapsed, Refractory, and Transformed Aggressive B-Cell Lymphoma.

Blood ◽

10.1182/blood.v108.11.3067.3067 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3067-3067 ◽

Cited By ~ 2

Author(s):

Lisa Hicks ◽

Rena Buckstein ◽

Joy Mangel ◽

Eugenia Piliotis ◽

Kevin Imrie ◽

...

Keyword(s):

Myocardial Infarction ◽

B Cell ◽

Overall Response Rate ◽

Response Rate ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Indolent Lymphoma ◽

Overall Response ◽

Grade 3 ◽

Aggressive B Cell Lymphoma

Abstract Background: Patients with relapsed or refractory aggressive B-cell lymphoma, or transformed indolent lymphoma can achieve long-term survival with high dose therapy and autologous stem cell transplant (HDT/ASCT), provided their disease is sensitive to salvage chemotherapy. Unfortunately, approximately 50% of patients are insensitive to standard salvage regimens. Objectives: This trial investigated whether adding Rituximab to ESHAP (etoposide, solumedrol, cytosine arabinoside, cisplatin) induction improved chemosensitivity. The primary outcome was overall response rate (CR + CRu + PR) to R-ESHAP. Secondary outcomes were toxicity, ability to undergo ASCT, progression free survival (PFS) and overall survival (OS). Methods: The protocol was approved by the local ethics review board and all patients provided informed consent. Eligible patients received ESHAP every 28 days with GCSF support until < 15% bone marrow involvement was achieved (2–4 cycles). Rituximab was given weekly x 8 weeks concurrent with the first 2 cycles of ESHAP. GCSF mobilized stems cells were collected on day 10–11 of cycle 1 or 2. Results: The trial was stopped early after the complete response (CR) rate at a planned interim analysis exceeded 40% (a pre-specified criteria for stopping the trial). Final results of 26 patients are presented. Median age was 55.5 years (range 42–64). Twelve patients had relapsed aggressive lymphoma, 2 had refractory disease and 12 had transformed indolent lymphoma. Twenty-two of 26 patients were stage III/IV. The overall response rate to R-ESHAP was 92% (95% CI 82% to 100%). Twelve patients (46%; 95% CI 27% to 65%) had a CR or unconfirmed CR. Grade 3–4 thrombocytopenia, neutropenia, and anemia occurred in 57%, 40%, and 15% of R-ESHAP cycles respectively. Grade 3–4 infections complicated 7% of cycles. Median follow-up was 17 months (range 2.9 to 43.2) from enrollment. Twenty-three of 26 patients (88%) were transplanted. Notable post-transplant toxicity included 5 cases of herpes zoster, 2 cases of bacterial pneumonia, 1 case of pulmonary aspergillosis, and 1 fatal case of pneumocystis carnii pneumonia (PCP). Three patients did not proceed to HDT/ASCT; 2 were refractory to R-ESHAP and 1 died of a myocardial infarction after induction chemotherapy but prior to ASCT. Fifteen of 23 patients who received ASCT remain in remission, 6 have relapsed. Seven patients have died, 4 of progressive disease, 1 of myocardial infarction, 1 of PCP, and 1 of accelerated Parkinson’s Disease. Median PFS and median OS have not yet been reached. Conclusions: In this single-arm, phase II study of relapsed or refractory aggressive B-cell lymphoma and transformed indolent B-cell lymphoma, R-ESHAP induction therapy resulted in a very high ORR (92%) and enabled a large percentage of patients (88%) to proceed to HDT/ASCT. Toxicity of the R-ESHAP regimen was acceptable, and its efficacy compared favorably with other salvage regimens reported in the literature, including R-ICE.

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Rituximab with High Dose Methotrexate in the Management of Primary Central Nervous System Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood.v124.21.3090.3090 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3090-3090 ◽

Cited By ~ 1

Author(s):

Roopesh R. Kansara ◽

Tamara Shenkier ◽

Joseph M Connors ◽

Alina S. Gerrie ◽

Richard Klasa ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

B Cell ◽

Initial Treatment ◽

Response Rates ◽

High Dose ◽

Time Interval ◽

High Dose Methotrexate ◽

Dose Methotrexate

Abstract Introduction: Outcomes of patient with primary central nervous system lymphoma (PCNSL) remain poor despite high-dose methotrexate (HDMTX)-based chemotherapy regimens. The addition of rituximab (R) to chemotherapy improves response rates and outcomes in patients with systemic B-cell non-Hodgkin lymphomas. However, R does not penetrate the blood-brain barrier, and therefore its impact in patients with PCNSL is unknown. With disappointing outcomes, in 2006, we routinely started adding R to HDMTX for the treatment of PCNSL. Herein, we evaluated the outcome of patients receiving HDMTX with or without R. Methods: Patients diagnosed with PCNSL (DLBCL histology only) between January 2000 and December 2013, and who were treated with at least one cycle of HDMTX, were identified in the Lymphoid Cancer Database. Since January 2000, patients with PCNSL in British Columbia have been treated with HDMTX 8 g/m2 every 2 weeks, pro-rated for creatinine clearance. Responding patients received a maximum of 10 cycles. Beginning in December 2006, rituximab 375 mg/m2 is given every 2 weeks with HDMTX for a total of 4 doses. Progression free survival (PFS) was defined as the time interval from date of diagnosis to first evidence of progression/relapse, death or last follow-up. Overall survival (OS) was defined as the time interval from date of diagnosis to death or last follow-up. Results: A total of 82 patients were identified. Median age at diagnosis was 61years (range 18-80), 42 (51%) were >60 years old, 48 (59%) were male, 18 (23%) had elevated LDH and 50 (61%) had performance status > 1. Median largest mass size was 4cm (range 1-9). Concurrent ocular (7 patients), leptomeningeal (3 patients), and spinal cord (1 patient) involvements were seen. For treatment, 55 (67%) received HDMTX and 27 (33%) received HDMTX+R. Patients received a median of 4 (range 1-9) HDMTX cycles, with no difference between R versus no R groups. Ten (12%) patients (6 HDMTX, 4 HDMTX+R) received whole brain radiotherapy (RT), as part of initial treatment due to chemo-intolerance. In 79 patients evaluable for response, the overall response rate to initial treatment was 55%: CR 40%, PR 15%, SD 5%, and PD 41%. There were no significant differences in the baseline characteristics or response rates between the two groups. A total of 14/32 patients (44%) relapsed after CR (all in the brain, including 1 to the contralateral eye) and 8/12 (67%) relapsed after PR (7 in brain, 1 to bilateral eyes). At 1st relapse/progression (N = 56), 39 (69%) patients received RT, 4 received repeat courses of HDMTX, 2 received high dose chemotherapy/autologous stem cell transplantation (ASCT) and 1 received temozolamide + R. 10 patients were managed supportively. Four patients had a systemic relapse without involvement of the CNS (1 Breast, 1 testis, 1 axilla and 1 scalp). They received R-CHOP (3), CHOP then R-GDP and ASCT (1). After a median follow-up of 5 years (range 0.1 to 12.7) in living patients, the 5-year OS was 38% (SE 6%), with no difference between patients treated with or without R (HR 0.81, 95% CI 0.40, 1.63; p= 0.55). The 5-year PFS was 20% (SE 5%), again with no difference between the two groups (HR 0.84, 95% CI 0.47, 1.48; p= 0.54). In the subset of 50 patients receiving > 4 cycles of chemotherapy (34 HDMTX, 16 HDMTX+R), the addition of rituximab did not impact PFS (p= 0.36) or OS (p= 0.08). In the subset of 72 patients who did not receive WBRT as part of initial therapy (49 HDMTX, 23 HDMTX + R), the addition of rituximab did not impact PFS (p= 0.48) or OS (p= 0.47). Conclusions: Our preliminary data shows no advantage to the addition of systemic R on the outcomes of PCNSL, consistent with its known poor CNS penetrance. Improved treatment modalities for PCNSL are still warranted. Disclosures Shenkier: F Hoffmann-La Roche: Other. Connors:F Hoffmann-La Roche: Other. Gerrie:F Hoffmann-La Roche: Other. Klasa:F Hoffmann-La Roche: Other. Savage:F Hoffmann-La Roche: Other. Sehn:F Hoffmann-La Roche: Other. Villa:F Hoffmann-La Roche: Other.

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Lenalidomide and Rituximab For The Treatment Of Patients With Relapsed Or Refractory Chronic Lymphocytic Leukemia: Results Of Planned Interim Analysis

Blood ◽

10.1182/blood.v122.21.5299.5299 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5299-5299 ◽

Cited By ~ 1

Author(s):

Michael Y. Choi ◽

Januario E. Castro ◽

Sheila Hoff ◽

Hongying Li ◽

Laura Rassenti ◽

...

Keyword(s):

Partial Response ◽

Interim Analysis ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Free Survival ◽

Safety And Efficacy ◽

Overall Response ◽

Grade 3

Abstract Based on data previously presented by our group demonstrating the safety and efficacy of lenalidomide (L) and rituximab (R) in the upfront setting, we are conducting an open-label, phase 2 trial single center trial to evaluate this combination as treatment for patients with relapsed or refractory CLL. Methods Patients started L at 5 mg per day and could escalate to 25 mg/day if tolerated. Patients received L for 21 of 35 days for cycle 1, then 21 of 28 days for cycles 2 to 7. Rituximab was started at the end of C1 at 50 mg/m2 on Day 29, 325 mg/m2 on day 31 and 33, then 375mg/m2 weekly x4 for cycle 2, and on day 1 for cycles 3-7. Patients who achieved a response but had residual disease after 7 cycles were given the option to continue single-agent L in a consolidative manner for 6 additional cycles. All patients received allopurinol 300mg daily and aspirin 81mg daily, unless contraindicated. The primary endpoint was overall response rate by iwCLL guidelines following 7 cycles. This abstract reports on the planned interim analysis of the safety and efficacy. Results By April 2013, 24 patients were enrolled and received treatment. 63% of patients were male (15/24). The median age at the start of study treatment was 67 years (range 53-83), with median 2.5 prior therapies (range 1-7). 75% (18/24) had CLL cells that expressed unmutated IgVH genes or high levels of ZAP-70. 25% (6/24) had unfavorable cytogenetics (del 17p or del 11q). 5 patients stopped therapy early due to toxicity. 2 patients stopped treatment due to grade 3 tumor flare reaction. 1 patient developed grade 4 tumor lysis requiring hemodialysis. 1 patient had grade 4 neutropenia within days of starting L. 1 patient developed a deep vein thrombosis during cycle 2 while off aspirin for transient thrombocytopenia. These patients tended to have a higher baseline absolute lymphocyte count, but this association did not meet statistical significance. Treatment was otherwise well tolerated. Neutropenia was the most common adverse event (AE), with grade 4 (by CTCAE 4) in 9 patients, and grade 3 in 6 patients out of 21 evaluable patients. There was a single instance of grade 4 thrombocytopenia, and 4 patients had grade 3 thrombocytopenia. 3 patients had grade 3 anemia. The only other grade 3 or higher AE was fatigue (5%). Of note, grade 2 superficial thrombophlebitis occurred in 3 patients. Out of the 20 patients whose primary endpoints were assessed, the overall response rate (ORR) was 70% (14/20) with 15% nodular partial response (3 patients) and 55% partial response (PR) (11 patients). 30% (6/20) were non-responders (NR). Only 1 of the 6 patients with NR had objective progressive disease (PD). The other 5 patients stopped treatment early due to toxicity and were designed as non-responders. Of the responder patients, 8 elected to receive an additional 6 months of consolidation lenalidomide. All maintained the same response without meeting objective criteria for either PD or complete response. After a median follow-up of 17 months from the start of treatment, there have been no deaths among the 24 patients. For the 20 evaluable patients, the median progression free survival (PFS) was 18.4 months and the median treatment free survival was 13.5 months.We did not find any significant association between response, toxicity, or PFS and any demographic or prognostic variable analyzed, including age, ZAP-70, IgVH mutation, cytogenetics, splenomegaly, or CLL cell immunophenotype. Conclusions The combination of lenalidomide and rituximab is an effective regimen for the treatment of patients with relapsed or refractory CLL with an ORR and PFS that rivals novel CLL therapies, especially for patients continued on lenalidomide consolidation therapy. The median PFS for all patients is in excess of 1.5 years after a median follow-up of 17 months. A subset of patients encountered adverse events requiring early treatment cessation, but only 1 patient progressed on treatment. Continued accrual will facilitate the identification of biologic or clinical factors that may predict such outcomes. Disclosures: Choi: Celgene: Research Funding. Castro:Celgene: Research Funding. Kipps:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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Long Term Outcomes of Rituximab, Temozolamide, and High-Dose Methotrexate for Lymphoma Involving the Central Nervous System

Blood ◽

10.1182/blood.v126.23.2701.2701 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2701-2701

Author(s):

Sarah Jordan Nagle ◽

Nirav N. Shah ◽

Alex Ganetsky ◽

Daniel J. Landsburg ◽

Sunita Dwivedy Nasta ◽

...

Keyword(s):

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Initial Response ◽

Response Assessment ◽

Response To Therapy ◽

High Dose ◽

High Dose Methotrexate ◽

Cns Involvement ◽

Dose Methotrexate

Abstract Background Management of patients (pts) with primary central nervous system lymphoma (PCNSL) and those with secondary CNS involvement by diffuse large B cell lymphoma (DLBCL) present a therapeutic challenge. There is no clear standard of care but traditionally initial treatment of PCNSL involves induction with intravenous high-dose methotrexate (HD-MTX) followed by consolidation including whole brain radiation therapy (WBRT), cytarabine, or autologous stem cell transplant. This approach has been associated with significant toxicities, especially the risk of cognitive dysfunction with WBRT. Treatment of secondary CNS involvement by DLBCL may depend on the extent of concomitant systemic disease, but HD-MTX is often the backbone of therapy. We report results of our institutional approach in pts with PCNSL and secondary involvement of the CNS by DLBCL using a prolonged course of rituximab, temozolamide, and HD-MTX (RTM) without consolidation. Methods We conducted a retrospective cohort study describing outcomes of pts with PCNSL or secondary CNS DLBCL who were treated on the RTM protocol. Eligible pts are treated with rituximab 375 mg/m2 on day 1 in combination with HD-MTX 8 g/m2 (days 1 and 15) and temozolamide 150 mg/m2 (days 1-5) in 28-day cycles. HD-MTX is administered with leucovorin rescue and adjusted for creatinine clearance. Initial response assessment is usually after 2 cycles with brain MRI. Once a complete response (CR) has been achieved, the day 15 HD-MTX is omitted from future cycles. Pts typically complete a total of 6-12 cycles, at the discretion of the clinician, without further planned consolidation. Descriptive and survival analyses using the Kaplan-Meier methodology were performed (STATA 13). The primary endpoints, overall survival (OS) and progression free survival (PFS) were estimated from the date of the first treatment with RTM to death, progression, or date of last follow-up. A log-rank test was utilized to compare OS/PFS between pts with PCNSL versus secondary CNS DLBCL. A Cox proportional hazard analysis was performed to evaluate the effect of patient level variables on OS. Clinical response was evaluated using International Workshop on Response Criteria for PCNSL (Abrey, J Clin Oncol 2005). Results We identified 46 pts who received RTM at our institution between 2009 and 2014. Twenty-seven (59%) pts had PCNSL and 19 (41%) pts had secondary CNS DLBCL. The median age at diagnosis was 61 years (range 21-85) with 50% males. Treatment was well tolerated. Two (4%) pts discontinued treatment prematurely and 7 (15%) pts required a dose reduction in HD-MTX due to toxicity. Toxicities included transaminitis, acute renal failure, infection, fatigue, and cytopenias. In pts with PCNSL, all received RTM as their initial treatment. Best response to therapy in this group was as follows: 19 (70%) had a CR, 3 (11%) had PR, 3 (11%) had SD and 2 (7%) had PD. The overall response rate was 81%. All patients with secondary CNS DLBCL had received prior systemic therapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone. Best CNS response to therapy in this group was as follows: 7 (37%) had CR, 2 (11%) had PR, 1 (5%) had SD, and 9 (47%) had PD. The overall response rate was 47%. For the entire cohort, the median OS was 41 months (m) and median PFS was 8 m. Compared with secondary CNS DLBCL, patients with PCNSL had a significantly longer median OS (54 m vs. 5 m; p<0.01) (Figure 1). PFS was also significantly longer for pts with primary versus secondary CNS DLBCL (22 m vs. 2 m; p=0.02) (Figure 2). Univariate cox analysis demonstrated that sex and age did not impact OS but pts who were in a CR or PR at initial response assessment compared to SD or PD had a hazard ratio for OS of 0.12 (95% CI: 0.05 to 0.29, P<0.01). Conclusions In our cohort, pts with PCNSL had excellent outcomes using a prolonged course of the RTM regimen without the toxicities of consolidation with radiation or high dose chemotherapy. These outcomes did not translate to pts with secondary CNS DLBCL, which may be consistent with the different biology and aggressive nature of this subgroup in addition to the prior therapies received. Early response assessment is vital to assess prognosis pts as those who respond within 2 cycles of therapy have an improved OS. This data suggests that RTM without further consolidation is an acceptable alternative regimen for PCNSL. Future prospective studies are needed to validate our findings. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Ganetsky: Onyx: Speakers Bureau. Dwivedy Nasta:Millenium: Research Funding; BMS: Research Funding. Mato:Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding; Pronai Pharmaceuticals: Research Funding; Celgene Corporation: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; TG Therapeutics: Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy. Schuster:Gilead: Research Funding; Janssen: Research Funding; Hoffman-LaRoche: Research Funding; Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Svoboda:Celgene: Research Funding; Seattle Genetics: Research Funding; Immunomedics: Research Funding; Celldex: Research Funding.

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Reponse-Adapted Study of Ibrutinib with Temozolomide, Etoposide, Doxil, Dexamethasone, and Rituximab (TEDDI-R) in Aggressive B-Cell Lymphomas with Secondary Involvement of the CNS

Blood ◽

10.1182/blood-2019-123552 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2875-2875

Author(s):

Mark Roschewski ◽

Christopher Melani ◽

Kieron Dunleavy ◽

Matthias Holdhoff ◽

Lode J. Swinnen ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

B Cell Lymphomas ◽

Overall Response ◽

Molecular Determinants ◽

Duration Of Response ◽

Cns Lymphomas ◽

Btk Inhibitors

Background: Aggressive B-cell lymphomas that secondarily involve the CNS (sCNSL) have a grave prognosis and no standard of care. Treatment includes chemotherapy that penetrates the CNS, such as high-dose methotrexate, but are relatively ineffective for extracranial disease. Diffuse large B-cell lymphomas with secondary CNS involvement are enriched for chronic active B-cell receptor signaling, and are responsive to BTK inhibitors. Ibrutinib is also active in other B-cell malignancies that spread to the CNS including MCL and transformed lymphomas. Ibrutinib achieves CNS penetrance and has a high overall response rate in CNS lymphomas, but duration of response is short and curative potential is limited (Grommes et al. 2017). Further, toxicities associated with ibrutinib can compromise outcomes when added to chemotherapy. Precise understanding of molecular determinants of response could enhance patient selection strategies. We developed a novel regimen that combines ibrutinib with temozolomide, etoposide, doxil, dexamethasone, and rituximab (TEDDi-R) for relapsed and refractory PCNSL. TEDDi-R achieved durable remissions in chemotherapy-refractory PCNSL (Roschewski et al. ASH 2018), but has been associated with opportunistic infections, including Aspergillus. Development of TEDDi-R continues with isavuconazole prophylaxis that inhibits clearance of ibrutinib. We opened a novel response-adapted clinical trial designed to study the safety and efficacy of TEDDi-R in sCNSL and elucidate molecular correlates of response to ibrutinib. Study Design and Methods: Phase II study of 29 evaluable patients with recurrent sCNSL [NCT03964090] Patients with untreated aggressive B-cell lymphomas are eligible if CNS lesions involve brain parenchyma Patients are first treated with a 14-day "window" of ibrutinib 560mg monotherapy with concomitant isavuconazole Response adapted: Patients with at least a 20% reduction in bidimensional masses following the 14-day ibrutinib window will receive ibrutinib with chemotherapy (TEDDi-R) for 4 cycles. Patients with less than a 20% reduction during the ibrutinib window will receive TEDD-R (without ibrutinib) for 4 cycles Primary endpoint: progression free survival (PFS) Secondary endpoints: Safety of TEDDi-R and TEDD-R Clinical activity after 14 days of ibrutinib monotherapy Best overall response rate of 4 cycles of TEDDi-R/TEDD-R Duration of response PKs and safety of ibrutinib and TEDDi-R with concomitant isovuconazole prophylaxis Overall survival Translational endpoints: Comprehensive molecular analysis of tumors using gene expression profiling, whole exome sequencing, and RNAseq analysis correlated with outcomeGenotype cell-free DNA in plasma and CSF correlated with clinical response Eligibility: Included Age ≥ 18Prior BTK inhibitors permitted, but patients known refractory to BTK will proceed directly with TEDD-RPatients with CLL or FL that have progressed in the CNS are considered to have transformed to an aggressive B-cell lymphoma and eligibleECOG performance status ≤2Adequate organ functionWilling to take appropriate contraception Excluded HIVInability to take isavuconazoleStatistical methods: Expected median PFS would be less than 4 months based on historical data. The goal is to improve to a median 10 months PFS. With 29 evaluable patients, there would be 90% power to determine a difference between a 4-month median PFS probability and an improved 10-month median PFS, with a one sided 0.05 alpha level test, using the method of Brookmeyer and Crowley. Confidence intervals and PFS probabilities will be reported, but no formal hypothesis test will be undertaken. Summary: This is a phase 2 study of TEDDi-R in aggressive B-cell lymphomas with secondary involvement of CNS that employs a novel response-adapted design for ibrutinib. The aim is to enhance selection of patients likely to benefit from ibrutinib and to investigate the molecular determinants of response to BTK inhibition. The study is open and the first patient has been enrolled. All patients will be treated at the NCI, but the development of TEDDi-R is supported by a consortium of regional academic centers who provide academic input, patient referrals, and data analysis. Current participating centers include Johns Hopkins University, George Washington University, University of Pennsylvania, University of Virginia, University of Pittsburgh and Penn State University. Figure Disclosures Dunleavy: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Swinnen:Pharmacyclics: Consultancy; AbbVie: Consultancy. Portell:Kite: Consultancy, Research Funding; Infinity: Research Funding; Roche/Genentech: Research Funding; Acerta/AstraZeneca: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Genentech: Consultancy, Research Funding; Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding. Svoboda:Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy; Seattle Genetics: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Celgene: Research Funding; Kite: Consultancy; Kyowa: Consultancy. Staudt:Nanostring: Patents & Royalties. OffLabel Disclosure: Ibrutinib used off-label for CNS lymphomas

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HLA-Matched Related (MRD) or Unrelated Donor (URD) Non-Myeloablative Hematopoietic Cell Transplantation (HCT) for Patients (pts) with Refractory and Relapsed Aggressive Non Hodgkin Lymphoma (NHL).

Blood ◽

10.1182/blood.v104.11.2307.2307 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2307-2307 ◽

Cited By ~ 1

Author(s):

L. Norasetthada ◽

M. B. Maris ◽

B. M. Sandmaier ◽

T. Gooley ◽

S. Forman ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Median Time ◽

Overall Response Rate ◽

Response Rate ◽

Cumulative Probability ◽

High Dose ◽

Unrelated Donor ◽

Myeloablative Conditioning ◽

Overall Response

Abstract There are few treatment options for pts with relapsed aggressive T and B cell NHL after failure of auto HCT and subsequent high dose allo HCT has resulted in high rates of non-relapse mortality (NRM). We evaluated utility of allo HCT after non-myeloablative conditioning for these pts to reduce NRM risks while exploiting graft versus tumor (GVT) effects. Between 12/1999 and 2/2004, 42 pts, median age 50 (range, 17–66) years, with refractory or relapsed aggressive NHL [diffuse large B cell (DLBCL) (n=32), T-cell anaplastic large cell (ALCL) (n=4), T-cell lymphoblastic (n=3), T- cell immunoblastic (n=2) and Burkitt’s (n=1)] were studied. Median time from dx to allo HCT and number of prior regimens were 40 (range, 7–222) months and 4 (range, 1–6), respectively. Twenty-seven pts (62%) had previous auto HCT: 24 had relapsed while 3 had planned auto HCT for cytoreduction before allo HCT. Median time from auto to allo HCT was 15 (range, 2–29) months. Allo conditioning consisted of 2 Gy TBI alone (n = 3 MRD) or with added fludarabine (90 mg/m2) (n = 39; 26 MRD, 13 URD) followed by mycophenolate mofetil and cyclosporin. PBSC (n = 41) or marrow (n = 1) were infused from MRD (n = 29) or URD (n = 13). At HCT, 18 pts were in complete remission (CR) and 24 had measurable disease [10 partial remission (PR) 14 untreated relapse and refractory]. All pts engrafted (see table). The overall incidences of grades II, III and IV acute GVHD were 33%, 15% and 4%, respectively. 2-year probability of chronic GVHD was 57%. Early death from aspergillosis occurred in 2 pts. Of the 18 pts given HCT in CR, 13 (72%) remained in CR after HCT, while 64% of pts (7/11) who were in PR and 23% of pts (3/13) who had relapsed/refractory disease at HCT, achieved CR. The overall response rate was 46%. Of the 24 pts who had relapsed after auto HCT, 2 died early, 11 (46%) achieved CR and 11 progressed after allo HCT. With a median follow up of 19 (range, 6–50) months, 20 of 42 pts (48%) (12 MRD, 8 URD) were alive: 18 in CR (43%) (10 MRD, 8 URD) and 2 with progressive disease. Twenty two pts died a median of 5 (range, 3–26) months after HCT: 14 from relapse and 8 from non-relapse causes (7/8 from infections + GVHD). Day 100, and 1-year NRM* were 10% and 15%, respectively. One year overall* (OS) and progression free survivals* (PFS), and relapse rates* were 63% (MRD: 62%; URD: 85%), 49% (MRD: 45%; URD: 62%) and 36% (MRD: 34%; URD: 38%), respectively. Allo HCT after non-myeloablative conditioning offers a therapeutic option for pts with relapsed aggressive NHL including those in relapse after auto HCT, especially when the disease can be cytoreduced before HCT. All pts (n=42) MRD (n=29) URD (n=13) Rel : Relapse; Ref : Refractory;*Cumulative probability Disease status at HCT 18 CR, 10 PR, 10 Rel, 4 Ref 12 CR, 8 PR, 6 Rel, 3 Ref 6 CR, 2 PR, 4 Rel, 1 Ref Overall response rate 11/24 (46%);(10 CR, 1 PR) 8/17 (47%);(7 CR, 1 PR) 3/7 (43%); (3 CR) CR at HCT, sustained CR 13/18 (72%) 8/12 (67%) 5/6 (83%) PR at HCT, sustained CR 7/11 (64%) 5/9 (56%) 2/2 (100%) Rel or Ref at HCT, sustained CR 3/13 (23%) 2/8 (25%) 1/5 (20%) Living pts status 18 CR, 2 PD 10 CR, 2 PD 8 CR Day 100 NRM* 10% 14% 0% 1 year NRM* 15% 21% 0% 1 year OS* 63% 62% 63% 1 year PFS* 49% 45% 62% 1 year Rel rate* 36% 34% 38%

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Cyclophosphamide Remains An Important Component of Treatment in CLL Patients Receiving Pentostatin and Rituximab Based Chemoimmunotherapy

Blood ◽

10.1182/blood.v112.11.43.43 ◽

2008 ◽

Vol 112 (11) ◽

pp. 43-43 ◽

Cited By ~ 1

Author(s):

Neil E. Kay ◽

Wenting Wu ◽

John C. Byrd ◽

Brian Kabat ◽

Diane F. Jelinek ◽

...

Keyword(s):

Overall Response Rate ◽

Response Rate ◽

Patient Characteristics ◽

Complete Response ◽

Hematologic Toxicity ◽

Overall Response ◽

Grade 3 ◽

Ecog Ps ◽

Experienced Grade

Abstract BACKGROUND: We have previously studied and reported that the combination of pentostatin (P, 2 mg/m2), cyclophosphamide (C 600 mg/m2) and rituximab (R 375 mg/m2) in previously untreated CLL is highly effective with an overall response (OR) rate of over 90% and a complete response rate (CR) of 41% (Blood109:405–411, 2007). We also found that this regimen can be effective even in older patients (>70 y), those with elevated beta-2 microglobulin levels, and patients with mildly reduced creatinine clearances (Cancer. 109:2291–2298, 2007). To determine whether similar benefit could be achieved without inclusion of an alkylating agent, we conducted a follow-up trial testing pentostatin and rituximab without cyclophosphamide and employing a higher pentostatin dose (4 mg/m2). METHODS: Eligible pts had documentation of active CLL by standard NCI-WG criteria, and were previously untreated. Treatment schema consisted of 6 cycles of pentostatin (4 mg/m2) and rituximab given every 21 days. Pentostatin was given on the first day of each cycle following infusion of rituximab. Rituximab was given at 100mg/m2 IV at day 1, then 375 mg/m2 IV on days 3 and 5 of the first treatment cycle. During cycles 2 to 6, Rituximab was given at 375 mg/m2 as a single IV infusion day 1 of week 4, 7, 10, 13 and 16. All patients were staged two months after completion of the 6 cycles of PR using the NCI-WG criteria. PATIENT CHARACTERISTICS: Overall, 33 patients were enrolled at Mayo Clinic and Ohio State University between July 2005 and February 2008. All 33 were eligible: 82% male, median age 65 (range: 45–81), with 9 (27%) being 70 years or older. 76% had a baseline ECOG PS of 0, and the rest were ECOG PS 1. Overall, 36% of patients had intermediate Rai risk (stage I–II) and 63% high Rai risk (stage 3–4) disease. Prognostic testing revealed that 36% were CD38+, 50% were Zap-70 +, and 39% had an unmutated IgVh status. Chromosome analysis by FISH found that 99% had detectable FISH panel defect, including 61%, 27% and 3% of patients with 1, 2, or 3 FISH detects, respectively. RESULTS: 28 of 33 patients (85%) completed therapy. While on treatment, 6 pts (18%) had a dose held or modified with 4 of these delays due to hematologic AE. For adverse events deemed at least possibly related to treatment, 4 (12%) pts experienced grade 3+ hematologic toxicity and 5 (15%) experienced grade 3+ non-hematologic toxicity. Out of all 33 enrolled patients, the overall response rate was 79% with 10 CR, 6 nPR, and 10 PR. At the time of this analysis, 29/33 patients are still alive with a median follow-up time of 14 months on surviving patients. To date 17/33 (52%) of patients have progressed with an estimated median time to progression of 12 months (95% CI: 8.5–21 months). 13/26 responders have progressed. Median duration of response is 12.5 months ((95% CI: 11–21 months). Finally, since eligibility were nearly identical and enrollment accrued at the same two academic centers, we compared the patient characteristics, response rates, and PFS of the 33 patients treated with PR to the 64 patients previously treated on our PCR trial. Patients in the two studies were generally similar with respect to demographic and prognostic characteristics, although patients in the PR trial had higher WBC and were less likely to be IgVH unmutated (Table). Although the differences in ORR and CR rate were not significantly different, the PFS appeared to be inferior in patients treated with PR as compared to PCR (12 months vs. 31 months; p=0.003). CONCLUSION: Although the PR regimen achieves a high OR response rate, the PFS appears inferior to PCR therapy. These findings suggest that increasing the purine nucleoside analogue dose does not eliminate the need to include cyclophosphamide in chemoimmunotherapy for patients with CLL. PCR Trial N=64 PR Trial N=33 P value Age, median(range) 63 years (38–80) 65 years (45–81) 0.34 ≥70 years(%) 28% 27% Male 77% 82% 0.61 Rai stage 0 5% 0 0.46 Rai stage I–II 42% 36% Rai stage III–IV 53% 64% White Cell Count, median(range) 79 × 109/L (11–519) 127 × 109/L (8–430) 0.04 <50 × 109/L 36% 28% 50–149 × 109/L 44% 25% >150 × 109/L 20% 47% Serum B2-microglobulin, median(range) 3.97 (1.8–13.5) 3.80 (2.0–8.2) 0.81 >2 × Upper Limit Normal(%) 57% 58% CD38 Positive 34% 36% 1.00 ZAP-70 Positive 36% 50% 0.26 IgVH Unmutated 71% 39% 0.004 FISH Normal, 11% 9% 13q- 35% 42% +12 21% 24% 6q- 2% 0 11q- 22% 18% 17p- 6% 3% other 3% 3% Overall Response Rate 91% 79% 0.12 Complete Response Rate 41% 30% 0.38 Median PFS 31 months 12 months 0.003

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A trial of gemcitabine (gems) in combination with cisplatin for treatment of recurrent/metastatic head and neck squamous cell carcinoma (HNSCC)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.15505 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 15505-15505

Author(s):

M. Yang ◽

H. Wang ◽

W. Wang ◽

T. Chiou ◽

P. Chen

Keyword(s):

Stable Disease ◽

Overall Response Rate ◽

Response Rate ◽

Performance Status ◽

Response Assessment ◽

Patient Treatment ◽

Open Label ◽

Overall Response ◽

Grade 3

15505 Aims: To determine the efficacy of gemcitabine in combination with cisplatin, and to assess the safety profile of the regimen as the first-line treatment in patients with recurrent/metastatic HNSCC. Methods: An open-label, non-comparative, multi-center phase II study for patients with histologically proven recurrent/metastatic HNSCC without prior treatment for their recurrent/metastatic disease. In this trial, 1250 mg/m2 gemcitabine was administered alone on day 1 and day 8 and 80 mg/m2 cisplatin would follow gemcitabine on day 8, to be repeated in cycles of 21 days until disease progression, intolerable toxicity, or consent withdrawal. Results: Between 04/2004 and 09/2005, 34 patients were enrolled in this study. 33 patients have completed the study treatment. Characteristics of the 33 patients: male- 33; median age- 51 years (range 38–65); 30 pts had a performance status (PS) of 0 or 1 and 3 had a PS of 2 (ECOG scale); histology: recurrent/metastatic HNSCC in all cases. Of the 33 patients, 25 were evaluable for response assessment. Partial response was observed in 8, stable disease in 10, and progressive disease in 7 patients. Overall response rate was 32% (95% Confidence interval 12%–52%). Grade 3/4 hematological toxicities included neutropenia in 12 pts, leukopenia in 11 pts, thrombocytopenia in 2 pts and anemia in 8 pts. Grade 3/4 nausea or vomiting was observed in 2 pts. Other toxicity was mild in the treatment. Patient treatment and follow-up are still ongoing. Conclusion: This study, with an overall response rate of 32% and a rate of stable disease of 40%, has shown a good activity with mild and acceptable toxicities of gemcitabine/cisplatin regimen in patients with recurrent/metastatic HNSCC. Survival and response analyses will be presented at the meeting. No significant financial relationships to disclose.

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