Recurrent Primary CNS Lymphoma Research Articles

Treatment Options for Recurrent Primary CNS Lymphoma.

Primary CNS lymphoma (PCNSL) constitutes a rare extranodal variant of non-Hodgkin lymphoma (NHL) with an annual incidence of 0.45/100,000. Given the paucity of large prospective clinical trials, there is no consensus treatment for refractory or relapsed (r/r) PCNSL, and available strategies are largely based on retrospective analyses. Patient age, performance status, previously administered treatment, duration of response, and molecular characteristics guide selection of salvage therapy. Patients with a good performance status (KPS >70), particularly ≤65 years, and adequate organ function should be considered for salvage polychemotherapy. Based on its high overall response rate even in the relapsed setting, we choose high-dose (≥ 3.5g/m2) methotrexate (HD-MTX) based regimens, e.g., R-MPV (rituximab, HD-MTX, procarbazine, and vincristine), for remission re-induction as long as patients were sensitive to first line HD-MTX-based regimens, especially when duration of previous response was ≥ 1 year. Following successful remission induction, we choose myeloablative chemotherapy (e.g., thiotepa, busulfan, cyclophosphamide) and subsequent autologous stem cell transplant in curative intent whenever feasible. Alternatively, conventional chemotherapy regimens (for example, monthly HD-MTX) or low-dose whole-brain radiation therapy (WBRT) are selected for consolidation in non-transplant candidates in complete remission. In cases of HD-MTX refractory disease or contraindications, we use pemetrexed; temozolomide/rituximab; high-dose cytarabine; or whole brain radiation for remission induction. Clinical trial participation is considered as well. Emerging therapies for upfront or salvage therapy under ongoing investigation include bruton tyrosine kinase inhibition (e.g., ibrutinib), immunomodulatory drugs (e.g., lenalidomide), immune checkpoint inhibitors (ICI, e.g., nivolumab), and chimeric antigen receptor T (CAR-T) cell therapy.

CAR-T Cell Therapy in Recurrent Primary CNS Lymphoma (PCNSL): A Phase 2 Clinical Trial (S27.009)

CAR-T Cell Therapy in Recurrent Primary CNS Lymphoma (PCNSL): A Phase 2 Clinical Trial (S27.009)

Intraventricular immune checkpoint inhibition with nivolumab in relapsed primary central nervous system lymphoma.

SUMMARY Intrathecal nivolumab combined with its systemic administration was recently found safe and effective in melanoma with leptomeningeal dissemination, prompting us to evaluate intraventricular nivolumab for recurrent primary CNS lymphoma (PCNSL) in an elderly patient unable to tolerate aggressive systemic polychemotherapy. Intraventricular nivolumab achieved a lasting (>12 months) complete remission including parenchymal lesions distant from cerebrospinal fluid spaces. No toxicities or adverse events related to the mode of administration were noted. Our case suggests intraventricular nivolumab is active in recurrent parenchymal PCNSL. Together with detected 9p24.1 gains this argues for further prospective evaluation, for which our treatment protocol provides a framework.

Phase Ib of Copanlisib in Combination with Ibrutinib in Recurrent/Refractory Primary CNS Lymphoma (PCNSL)

BACKGROUND: PCNSL is an aggressive primary brain tumor with median progression free survival (PFS) after upfront methotrexate-based chemotherapy of 2-3 years. Outcome and treatment options are poor for recurrent/refractory (r/r) disease. This trial combines the pan-PI3K inhibitor copanlisib with Ibrutinib in patients with r/r PCNSL. METHODS: Eligible patients had r/r PCNSL, age≥18, ECOG≤2, normal end-organ function, and an unrestricted number of CNS directed prior therapies. Ibrutinib was given orally daily; copanlisib intravenously on days 1, 8, and 15 of each 28-day cycle. RESULTS: Six patients have been enrolled so far and received copanlisib at 60 mg and ibrutinib at 560 mg. Median age was 68 (range 50-77); 3 were women. Median ECOG was 1 (0: 2, 1: 3, 2: 1). All had recurrent parenchymal disease. Three had additional cerebrospinal fluid (CSF) involvement. Two had received prior single-agent ibrutinib. Initially, no prophylactic antimicrobial treatment was required. PCP prophylaxis was made mandatory after one patient developed PCP pneumonia leading to a grade 5 lung infection. Four patients are still on trial and one withdrew due to personal choice. Two grade 4 adverse events were observed in 2 patients (LFT elevation, lymphopenia); four grade 3 events in 3 patients (rash, lymphopenia, LFT elevation). The most common toxicities at any grade were transient, infusion-related hyperglycemia and hypertension. No Aspergillus infections have been observed. Enrollment into the next dose level (copanlisib 60 mg, ibrutinib 840 mg) is ongoing. After a median follow-up of 180 days (range 46-249), all patients were evaluated for response with an overall response rate of 67% with 1 CR, 3 PR, 1 SD and 1 PD as best response. CONCLUSION: Treatment with copanlisib and ibrutinib in patients with PCNSL has manageable adverse events after initiation of mandatory PCP prophylaxis. Clinical response was seen in 67% of patients. Disclosures Grommes: Squipps: Speakers Bureau; Kite: Consultancy; BTG: Consultancy. OffLabel Disclosure: The combination of the BTK inhibitor ibrutinib and the pan PI3K inhibitor copanlisib in recurrent PCNSL will be discussed

Recurrent Primary CNS Lymphoma Presenting with Central Neurogenic Hyperventilation (P6.283)

Recurrent Primary CNS Lymphoma Presenting with Central Neurogenic Hyperventilation (P6.283)

Recurrent Primary CNS Lymphoma Presenting with Central Neurogenic Hyperventilation

Background: Tumor-induced Central Neurogenic Hyperventilation (CNH) is exceedingly rare, about half resulting from Primary CNS Lymphoma (PCNSL) despite their rarity. Results: We present a 75 year-old, immunocompetent woman with recurrent PCNSL leading to CNH. She was initially diagnosed with PCNSL via biopsy of the single enhancing left caudate focus among diffuse, nonenhancing CNS infiltrative disease without diffusion restriction or CSF or intraocular dissemination. She received 5 cycles of biweekly rituximab and methotrexate, initially dosed at 3.5 gm/m2 with procarbazine and vincristine, then dosed at 8 gm/m2 with monthly temozolomide 150 mg/m2. Repeat brain MRI revealed no residual enhancement with confluent subcortical nonenhancing signal without brainstem involvement suggesting methotrexate-related leukodystrophy. Two weeks after cytarabine consolidation, she presented with intractable emesis without gastrointestinal cause. A week later, she developed marked tachypnea without cardiopulmonary etiology. Blood glasses revealed respiratory alkalosis (maximal pH=7.67, respiration=27, pO2=241; minimum pCO2=10). She remained otherwise neurologically intact. For suspicion of CNH, she was intubated and brain MRI revealed progressive nonenhancing disease without restricted diffusion extending periventricularly from dorsal midbrain to vermis. CSF profile revealed normal protein (40 mg/dL), RBC 97/µL, WBC 3/µL (88% lymphocytes) with negative bacterial cultures, toxoplasma IgG and HSV, JC, CMV, EBV and JC PCRs. Flow cytometry and cytology revealed no lymphoma cells. Brain and body PET revealed avid FDG-uptake in the new periaqueductal nonenhancing tumor, confirming lymphoma recurrence; no extracranial disease was evident. Her CNH resolved though remission was only brief following posterior fossa radiation (30Gy, 17fx), dexamethasone 40 mg/day, and off-label nivolumab 3 mg/kg q 2 weeks. Repeat brain MRI revealed diffuse cerebral nonenhancing disease progression at 4 months after recurrence. She died shortly after transfer to hospice. Conclusion: This represents the first recurrent PCNSL leading to CNH, which was a presenting symptom in all prior PCNSL cases reported and lead to death in the majority.

High-dose cytarabine salvage therapy for recurrent primary CNS lymphoma.

Treatment of recurrent primary CNS lymphoma (PCNSL) though not standardized most often utilizes whole brain radiotherapy, re-challenge with high-dose methotrexate, or administration of an alkylating chemotherapy. High-dose cytarabine (HD-araC) has been advocated as an active agent in PCNSL but limited information exists regarding single agent activity in the recurrent setting. A retrospective review of 14 patients (10 males, 4 females: median age 60 years) with recurrent PCNSL treated at second recurrence with single agent HD-araC. HD-araC was administered at 3gm/m(2) over a 3-h infusion every 12 h for a total of 4 doses (defined as a cycle of therapy). GM-CSF was administered at conclusion of HD-araC. Patients were clinically and radiographically evaluated every 4-weeks. Common toxicity criteria Grade 3 or 4 toxicity included thrombocytopenia (11 patients; 79%), anemia (10; 71%), fatigue (8; 57%), mucositis (8; 57%), neutropenia (8; 57%) and neutropenic fever (5; 36%). No patient discontinued therapy due to toxicity nor were there any treatment-related deaths. Best response to HD-araC was stable disease in 6 patients (43%), partial response in 5 (36%) and progressive disease in 3 (21%). Median progression free survival 3 months (range 2-5 months; 95% CI 2-4 months) and progression free survival was 0% at 6-months. Median survival after onset of HD-araC was 12 months (range 3-18+ months; 95% CI 3-15 months). Single agent HD-araC has limited activity in recurrent PCNSL and is associated with significant toxicity in this small retrospective study.

ATCT-10HIGH-DOSE CYTARABINE SALVAGE THERAPY FOR RECURRENT PRIMARY CNS LYMPHOMA

BACKGROUND: Treatment of recurrent primary CNS lymphoma (PCNSL) though not standardized most often utilizes whole brain radiotherapy, re-challenge with high-dose methotrexate, or administration of an alkylating chemotherapy. High-dose cytarabine (HD-araC) has been advocated as an active agent in PCNSL but limited information exists regarding single agent activity in the recurrent setting. PATIENTS AND METHODS: A retrospective review of 14 patients (10 males, 4 females: median age 60 years) with recurrent PCNSL treated at second recurrence with single agent HD-araC. HD-araC was administered at 2gm/m2 over a 3-hour infusion every 12 hours for a total of 4 doses (defined as a cycle of therapy). GM-CSF was administered at conclusion of HD-araC. Patients were clinically and radiographically evaluated every 4-weeks. RESULTS: Common toxicity criteria Grade 3 or 4 toxicity included thrombocytopenia (11 patients; 79%), anemia (10; 71%), fatigue (8; 57%), mucositis (8; 57%), neutropenia (8; 57%) and neutropenic fever (5; 36%). No patient discontinued therapy due to toxicity nor were there any treatment-related deaths. Best response to HD-araC was stable disease in 6 patients (43%), partial response in 5 (36%) and progressive disease in 3 (21%). Median progression free survival 3 months (range 2-5 months; 95% CI 2-4 months) and progression free survival was 0% at 6-months. Median survival after onset of HD-araC was 12 months (range 3-18+ months; 95% CI 3-15 months). CONCLUSIONS: Single agent HD-araC has limited activity in recurrent PCNSL and is associated with significant toxicity in this small retrospective study.

Lenalidomide monotherapy as salvage treatment for recurrent primary CNS lymphoma.

The prognosis of patients with primary CNS lymphoma (PCNSL) who fail high-dose methotrexate (HD-MTX)–based chemotherapy remains poor, particularly in older individuals, and improvements in salvage chemotherapy are needed. The few cytotoxic agents available for this condition demonstrate limited efficacy.1 Lenalidomide is an immunomodulatory agent, derived from thalidomide, with antiproliferative activities that might act by modifying the tumor microenvironment and activating cytotoxic T and natural killer cells.2 Its efficacy has been established in multiple myeloma and more recently as a single agent or in combination with rituximab in several types of non-Hodgkin lymphomas. In refractory or relapsed systemic diffuse large B-cell (DLBC) lymphomas, lenalidomide exhibited a 28%–35% response rate with a good safety profile.3,4 Interestingly, pomalidomide, a lenalidomide analog, showed activity against CNS lymphoma in murine models and is currently investigated in a phase I study (NCT 01722305). Although little is known about the capacity of lenalidomide to cross the blood–brain barrier,5 this drug appears to be potentially active in PCNSL. The objective of this retrospective case series was to determine the response rate to a standard dose of lenalidomide. Acknowledgment: The authors thank the LOC French National Network (INCa) for its support.

Salvage therapy with bendamustine for methotrexate refractory recurrent primary CNS lymphoma: a retrospective case series

There is comparatively limited therapy for recurrent primary central nervous system lymphoma (PCNSL). Salvage therapies include re-challenge with high-dose methotrexate (HD-MTX), whole brain radiotherapy, temozolomide, topotecan and premetrexed. Bendamustine is a novel bifunctional alkylator with established activity in B cell systemic lymphomas but never previously evaluated in PCNSL. The objective of the current study was to assess response and toxicity of bendamustine in recurrent PCNSL following prior salvage therapy in a retrospective case series. Twelve adults [six males; six females: median age 59 years (range 43-74)] with HD-MTX refractory recurrent PCNSL were treated with bendamustine. All patients were treated at second recurrence following failure of prior salvage therapy. A cycle of bendamustine was defined as two consecutive days of treatment (100 mg/m(2)/day) administered once every 4 weeks (maximum number of cycles 6). Toxicities seen were Grade 2 (24 episodes in 10 patients) and 3 (10 episodes in 5 patients) only and included lymphopenia (8 patients), hyperglycemia (7 patients), fatigue (7 patients) and nausea (4 patients). The median number of cycles of therapy was 3.5 (range 1-6). Radiographic response was progressive disease in 5 (42%), stable disease in 1 (8%), partial response in 3 (25%) and complete response in 3 (25%). Median progression free survival (PFS) was 3.5 months (range 1-14 months) and 6-month PFS was 33 %. In this small retrospective series of select patients with recurrent PCNSL refractory to HD-MTX, bendamustine appears to have modest single agent activity with manageable toxicity. Confirmation in a larger series of similar patients is required.

Methotrexate re-challenge for recurrent primary central nervous system lymphoma

The prognosis of primary CNS lymphoma (PCNSL) recurring after methotrexate is poor (objective response rates [ORR] = 26-53 %; 1-year overall survival [OS] = 35-57 %). Salvage PCNSL chemotherapies have been based on the use of different agents to avoid cross-resistance; however, methotrexate is the most active agent in PCNSL, and methotrexate re-challenge may be an effective strategy for recurrent disease. We report our experience with methotrexate re-challenge in PCNSL. We reviewed 39 patients with histologically confirmed PCNSL who responded to methotrexate at initial diagnosis, experienced disease relapse and received methotrexate re-challenge. At the time of re-challenge, median age was 66 and median Karnofsky performance score (KPS) was 70. Median time from initial diagnosis was 26 m. Twenty-six patients were at first relapse and 13 at second or later relapse. At re-challenge, methotrexate was given in combination with other agents to 33 patients and as a single agent to six. The objective response rate was 85 %, with a complete response in 29 (75 %) patients, partial response in four (10 %) and disease progression in six (15 %). At median follow-up of 26 m, the median progression-free survival was 16 m; 1-year OS was 79 % (95 % CI 63-89) and median OS was 41 m. KPS was a prognostic factor for progression free survival (p = 0.04). In this population selected by previous methotrexate response, methotrexate re-challenge was a safe and effective strategy, indicating chemosensitivity was retained. Efficacy compared favorably to other salvage treatments suggesting methotrexate re-challenge should be considered in recurrent PCNSL patients who previously responded to methotrexate.

High-dose chemotherapy (HDC) followed by autologous stem cell transplant (ASCT) for recurrent/progressive CNS lymphoma.

2089 Background: In two reports by Soussain et al, promising efficacy was observed in recurrent primary CNS lymphoma with induction cytarabine/VP-16 (CYVE) followed by HDC-ASCT (busulfan, thiotepa and cyclophosphamide [BTC]), but significant toxicity, mainly from CYVE, has limited widespread use. We report our experience with HDC-ASCT with alternative induction regimens. Methods: Retrospective review of pts with recurrent/refractory non-Hodgkin lymphoma (NHL) with CNS involvement treated with HDC-ASCT (2000-present). Results: Seventeen pts met inclusion criteria: med age= 58 (41-65); 9 were women; med KPS prior to transplant= 90 (range 70-100). At initial presentation, 10 had primary CNS lymphoma (ocular: 1); 7 had systemic NHL without CNS involvement; 1 had both systemic and CNS disease. Pts had been heavily pre-treated. Among those with PCNSL, high dose MTX was used in all pts and WBRT in 4. Two pts had received a previous HDC-ASCT. Among systemic NHL pts, various regimens were used, mostly R-CHOP(4), but also R-EPOCH (1), CVP (1), ICE (1) and CODOX-M (1). At CNS recurrence, pts received various induction regimens prior to HD-ASCT: high-dose methotrexate (MTX)-based chemotherapy (N= 13), cytarabine-based regimens (N=2), and other (N= 2). All pts achieved a CR or near CR prior to HDC-ASCT. Harvesting was obtained with G-CSF alone in 9 pts; 8 required plerixafor. Two pts failed mobilization N=15 received HDC-ASCT. The HDC consisted of BTC (N=13); 1 received BEAM and 1 received reduced intensity fludarabine, melphalan and alemtuzumab. Eight pts experienced a grade III or IV toxicity – most commonly fatigue, febrile neutropenia, and infection. One previously transplanted pt died from sepsis. With a med follow-up of 11 months, post-transplant med-PFS has not been reached. The 12m PFS was 92% (95% CI 56-98). Because no patient has progressed, the OS was identical to PFS. Conclusions: HDC-ASCT was a highly effective salvage approach in this population of recurrent/refractory CNS lymphoma. To reduce the risk of harvesting failure at the time of recurrence, harvesting stem cells at the time of initial treatment could be considered in pts with high risk for relapse.

Multicenter phase II trial of temozolomide (TMZ) and rituximab (RIT) for recurrent primary CNS lymphoma (PCNSL): North American Brain Tumor Consortium (NABTC) study 05-01.

2039 Background: Salvage chemotherapy for PCNSL has been poorly characterized, with few, mostly retrospective studies reporting objective response rates (RR) of 26-53% and 1y overall survival (OS) ...

Rituximab monotherapy for patients with recurrent primary CNS lymphoma

Rituximab, a chimeric monoclonal antibody against the CD20 antigen, increased survival when it was added to chemotherapy for patients with systemic, CD20+ diffuse large B-cell (DLBCL) non-Hodgkin lymphoma (NHL). Consequently, it is now a standard component of the treatment for these patients. Approximately 90% of primary CNS lymphomas (PCNSL), a rare extranodal variant of NHL, are CD20+ DLBCL. Rituximab has been incorporated into some treatment regimens for newly diagnosed and relapsed PCNSL, although it is not known whether this agent will improve outcomes to the extent that it has for patients with systemic DLBCL.1,2 Rituximab may not traverse the normal blood–brain barrier (BBB) and this could limit the effectiveness of this agent in PCNSL. Rituximab concentrations in CSF are 0.1% of plasma levels when it is administered at a standard IV dose of 375 mg/m2, suggesting poor BBB penetration.3 Moreover, in a report of 4 patients with PCNSL administered I123-labeled rituximab, there was weak tumor uptake in only one out of 4 patients.4 However, in another study of the 90Y-labeled anti-CD20 antibody ibritumomab tiuxetan target accumulation of the antibody was observed in 4 out of 6 patients …

Enhanced Delivery of Rituximab In Combination with Methotrexate-Based Blood-Brain Barrier Disruption for Patients with Newly Diagnosed Primary CNS Lymphoma.

AbstractAbstract 2792 Introduction:Primary CNS lymphoma (PCNSL) is a rare, aggressive, primarily large B-cell lymphoma confined to the CNS and/or eyes at presentation. High-dose (HD) methotrexate (MTX) - based chemotherapy is standard of care in PCNSL and when combined with enhanced delivery results in extended survival without cognitive loss. The addition of rituximab to HD MTX regimens for B-cell PCNSL is widely used primarily by analogy to the positive results attained in systemic B-cell lymphomas. However, recent pre-clinical and clinical use of single agent rituximab provides stronger rationale. Efficacy has been shown using single agent rituximab in nude rats with intracerebrally implanted MC116 human B-cell lymphoma cells, and in patients with recurrent PCNSL by using 111In-ibritumomab to assess delivery and 90Y-ibritumomab to assess efficacy. Next, safety and efficacy of enhanced delivery of rituximab with MTX-based blood-brain barrier disruption (BBBD) was shown in patients with recurrent PCNSL. Based on these results, we treated patients with newly diagnosed PCNSL with rituximab in combination with MTX-based BBBD. Methods:IRB permission was obtained to retrospectively evaluate patients with newly diagnosed B-cell PCNSL, treated with rituximab in combination with MTX-based (intra-arterial [i.a.]) BBBD chemotherapy as first-line treatment. Treatment consisted of MTX (2500mg/day, i.a.) and carboplatin (200mg/m2/day, i.a.) with BBBD, for 2 consecutive days every 4 weeks for up to one year. Rituximab (375mg/m2, i.v.) was given every 4 weeks, 12 hours prior to the MTX with BBBD treatment. Objective response rate, progression free survival (PFS), overall survival (OS), and toxicities were evaluated. Results:Twelve patients (7 female, 5 male) were treated between April 2003 and October 2008. The median age was 65 years (min 49, max 75); 10 patients were older than 60 years. The median Karnofsky Performance Score (KPS) prior to treatment was 55 (min 20, max 80). All patients had brain parenchyma involvement at presentation. Additionally, CSF cytology was positive in 2 patients and one patient had ocular involvement. One patient with pre-existing cardiac disease died 2 weeks after initiation of MTX without BBBD due to myocardial infarction and was not evaluable for response. The overall response rate was 83% (7 CR, 1 CRU, 2 PR, 1 SD). The median PFS was 3.47 years (95% CI: 0.42, not yet attained) and the 2-year PFS in this cohort is 73%. The median OS was 4.42 years (95% CI: 0.28, not yet attained). Eight patients who attained CR or CRU were alive at data-cut-off; 6 of the 8 patients remain in CR 2 years or more after diagnosis. The most frequent toxicities were hematologic. Eight (67%) patients developed grade 3 or 4 hematologic toxicity and 7 (58%) developed grade 3 infection. Conclusions:We previously reported a 2-year PFS of 50% with 25% survival at 8.5 years in 149 newly diagnosed PCNSL patients treated with MTX-based BBBD without rituximab. The addition of rituximab shows manageable toxicity and provides sustained duration of CR in newly diagnosed PCNSL, with 10 of 12 patients over 60 years old and a median KPS of 55. These pilot data suggest the 2-year PFS may be increased to 70% or more with the addition of rituximab to MTX-based BBBD chemotherapy. A multi-center phase II prospective study is underway. Disclosures:No relevant conflicts of interest to declare.

Phase II trial of recurrent primary CNS lymphoma (PCNSL) treated with pemetrexed

2075 Background: Using high-dose methotrexate based regimens; median survival for patients with PCNSL is up to 60 mo. Approximately 50% of patients will relapse within 2 yrs. No standard therapy exists for relapsed patients but numerous regimens have been used with variable results. In addition to inhibiting dihydrofolate reductase, pemetrexed targets other sites of inhibition, giving it a broader spectrum of activity than methotrexate. This suggested that pemetrexed may be effective in PCNSL and lead to our use in a phase II trial. We update our results further substantiating the use of pemetrexed in PCNSL. Methods: All patients were treated with pemetrexed 900 mg/m2 every 3 weeks. Patients received dexamethasone 4 mg bid on the day before, the day of, and the day after each infusion of pemetrexed and supplemental folic acid and B12. Eligibility criteria for PCNSL patients included failure of at least 1 prior chemotherapy regimen. Patients had to be > 18 years of age with KPS > 60. Adequate bone marrow, liver, and renal function were required. MRI was done every 6 weeks (1 cycle) and for patients who attained a CR, a maximum of 6 doses was given. Results: To date, 8 patients with recurrent PCNSL have been treated on this trial after signing IRB approved consent. All patients had large B Cell lymphoma except one had a low grade lymphoma. Conclusions: We report our experience of pemetrexed in 8 patients with recurrent PCNSL; all of whom had a radiographic response except the patient with low grade lymphoma who had SD. 3 patients had sustained CR, 1 of whom responded to a re-challenge with 2 other relapses. 62% of the patients had 6 or more cycles of therapy. This regimen is easy to administer with relatively minimal toxicity and should be considered for patients with relapsed PCNSL. Patient Characteristics Patient Age/ Sex # Prior therapy Response to pemetrexed # doses Length of Response Current status Toxicity 1 81/M 2 PR 2 Transient improvement after 1 dose then PD Deceased from Tumor gr 4: thrombocytopenia gr 3 infection, anemia, and leukopenia 2 52/F 4 PR 3 Transient improvement after 2 doses then PD Deceased from Tumor gr 4: thrombocytopenia and anemia gr 3: leukopenia and infection 3 72/M 1 PR 7 Major PR after 2 doses and sustained Deceased from sepsis/ unknown gr 3: cytopenias after 5th cycle 4 * 69/M 2 CR after 2 cycles 6 5 months Deceased from tumor gr 4: leukopenia gr 3: pain and infection 5 56/F 1 CR after 2 cycles 7 CR after 2 doses and sustained for over 11 months Alive No toxicity 6 69/M 1 SD 3 SD for 2+ months (time on study) Deceased from infection gr 3: leukopenia and thrombocytopenia 7 49/M 1 SD 6 SD for 4 months (time on study) Alive gr 3: transaminitis 8 39/M 1 CR 8 CR after 4 cycles and sustained for 3 months Alive No toxicity * At disease progression was treated with temodar and rituxan with progressive disease; retreatment with pemetrexed led to another CR, he again relapsed 4.5 mo later and responded to pemetrexed before he decided to stop treatment. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Lilly Oncology

Intensive Chemotherapy Followed by Hematopoietic Stem-Cell Rescue for Refractory and Recurrent Primary CNS and Intraocular Lymphoma: Société Française de Greffe de Moëlle Osseuse-Thérapie Cellulaire

The prognosis of relapsing primary CNS lymphoma (PCNSL) is poor. We report the results of a prospective multicenter trial of intensive chemotherapy followed by autologous hematopoietic stem-cell rescue (IC + HCR) in immunocompetent adult patients with PCNSL or intraocular lymphoma (IOL) after failure of high-dose methotrexate-based treatment. Salvage treatment consisted of two cycles of high-dose cytarabine and etoposide (CYVE). Intensive chemotherapy combined thiotepa, busulfan, and cyclophosphamide. Forty-three patients (median age, 52 years; range, 23 to 65 years) were included, with relapse (n = 22), refractory disease (n = 17), or a partial response to first-line treatment (n = 4). The response to CYVE was not assessable in three cases because of treatment-related death. Twenty patients (47%) were chemosensitive to CYVE: 15 of them proceeded to IC + HCR. IC + HCR was also administered to 12 patients who did not respond to CYVE. All but one of the 27 patients who underwent IC + HCR entered complete remission. With a median follow-up of 36 months, the median overall survival was 18.3 months in the overall population, and 58.6 months among patients who completed IC + HCR. The respective median progression-free survival (PFS) times after IC + HCR were 11.6 and 41.1 months. The 2-year overall survival probability was 45% in the whole population and 69% among the 27 patients who received IC + HCR. The 2-year PFS probability was 43% among all the patients and 58% in the IC + HCR subpopulation. IC + HCR is an effective treatment for refractory and recurrent PCNSL.

F-18-labeled fluorodeoxyglucose positron emission tomography for evaluation of disease extent, response to treatment and follow-up in primary CNS lymphoma

2015 Background: Fluorine-18-labeled (18F) fluorodeoxyglucose (FDG) positron emission tomography (PET) has demonstrated remarkable sensitivity in the detection and follow-up of malignant lymphoma. The aim of this study was the prospective evaluation of potential benefits of FDG-PET including whole-body PET for evaluation of disease extent, response to treatment and follow-up of patients with primary CNS lymphoma (PCNSL). Methods: Extent of disease and response to therapy were evaluated using homologous scans of MR imaging and a total number of 36 18F-FDG-PET examinations in 10 immunocompetent patients with newly diagnosed or recurrent PCNSL before and repeatedly during treatment and follow-up. Results: In 4 of 10 patients before treatment, MRI findings lacked a PET correlative, and in two patients each one additional lesion not visualized by MRI was detected by PET. Additional systemic spots of activity in whole-body PET were found in two patients and confirmed as asymptomatic lymphoma manifestations by computed tomography (CT) in one patient. Under treatment, tumor response was congruent on PET and MRI in 4 of 6 patients. In two patients, however, PET indicated complete disappearance of vital tumor while findings persisted on MRI. During follow-up in a series of 5 patients, pathologic FDG-uptake had been found in one patient on PET 34 weeks after therapy and 9 weeks before relapse was diagnosed on MRI. In another patient, relapse was suspected on PET 76 weeks after therapy without a correlative on MRI performed 2 and 6 weeks thereafter. Conclusions: In PCNSL, FDG-PET may contribute additional information regarding the extent of disease and response to treatment. Relapse can probably be detected earlier than with MRI. No significant financial relationships to disclose.

Salvage therapy and late neurotoxicity in patients with recurrent primary CNS lymphoma treated with a modified ProMACE-MOPP hybrid regimen

We report the efficacy of salvage therapy with a modified ProMACE-MOPP combined with radiation in patients with primary central nervous system lymphoma (PCNSL). Thirty-two immunocompetent patients were treated with a regimen of pirarubicin, cyclophosphamide, etoposide, vincristin, and methotrexate (MTX: 500 mg/m2) administered in 21-day cycles. Patients received 20 Gy of whole-brain radiotherapy after three cycles of chemotherapy. A single cycle of chemotherapy was repeated every four months for two years. Nine patients with CNS relapse were retreated with additional cycles of the ProMACE-MOPP hybrid regimen with a 90% objective response rate. Median complete response (CR) duration was 13.2 months and median survival time (MST) for the nine patients treated after initial relapse was 30 months. One of 17 patients (5.8%) who had less than 20 Gy of whole brain irradiation developed dementia. In contrast, six of seven (85.7%) patients who had more than 30 Gy of whole brain radiotherapy became demented. Maintaining a moderate dose of MTX, while adding chemotherapeutic agents and 20 Gy of whole brain radiation therapy, improved disease control and overall survival and lowered the incidence of delayed neurologic toxicity in patients with PCNSL. Additional treatment with a ProMACE-MOPP hybrid regimen is still effective for relapsed disease.

Penetration of Yttrium-90-Labeled Ibritumomab Tiuxetan (Zevalin™) into Primary CNS Lymphoma.

Background: Salvage treatment has not yet been established in primary CNS lymphoma (PCNSL). The introduction of anti-CD20 monoclonal antibody rituximab expanded treatment options in systemic B-cell lymphoma. Due to its large molecular size, rituximab poorly penetrates the blood-brain-barrier (BBB) limiting its use in PCNSL. According to FDG-PET investigations, however, the BBB is initially leaky in PCNSL and reconstitutes after therapy-induced tumor shrinkage. We treated patients with relapsed/resistant PCNSL with a single course of Y-90 anti-CD20 antibody ibritumomab tiuxetan and evaluated the penetration of the antibody into the tumor.Methods: Immunocompetent patients with histologically confirmed, therapy resistant or recurrent PCNSL after at least one pretreatment, and adequate cardiac and bone marrow function were treated with rituximab 250 mg/m2 on day -7 and day 0, followed by Y-90-ibritumomab tiuxetan 15 MBq/kg IV. In three patients single photon emission computed tomography (SPECT) target imaging with gamma-emitting 111-Indium-ibritumomab tiuxetan was performed repeatedly 4 - 168 hours after Y-90-ibritumomab tiuxetan. Response evaluation by contrast-enhanced magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) was scheduled before, one month and two months after treatment as well as every three months thereafter in responders.Results: Seven patients with a median age of 46 years (range 40–63) and a median number of 4 (range 1–6) previous therapies received antibody treatment. SPECT indicated target accumulation in the tumor starting 48 hours and still ongoing 7 days after injection of 111-Indium-ibritumomab tiuxetan. Response was observed in four of seven patients: one uncertain complete response (uCR) lasting 18+ months, two CR (0.5 and one month), and one partial response (0.5 months). Relapse usually occurred distant of target lesions. Three patients had disease progression. Toxicities were leukopenia CTC grade 3/4 (n=6), pneumonia grade 3/4 (n=2) with one fatal outcome, and thrombocytopenia grade 3/4 (n=6).Conclusions: We provide first evidence of Y-90-ibritumomab tiuxetan penetration into PCNSL with target accumulation of the antibody in SPECT. However, responses were mostly of short duration in this heavily pretreated patient cohort with relapses occurring distant of target lesions. Hematotoxicity up to CTC grade 4 was the most common side-effect. Further investigation within a phase II study is warranted.