Prophylactic Intrathecal Methotrexate Research Articles

NCMP-05. CLINICAL AND RADIOGRAPHIC IMPROVEMENT WITH REPLACEMENT OF FOLATE METABOLITES IN A PATIENT WITH INTRATHECAL METHOTREXATE-INDUCED MYELOPATHY

Abstract Methotrexate (MTX)-induced myelopathy is a rare but serious adverse effect of intrathecal (IT) MTX, which may mimic subacute combined degeneration (SCD). MTX disrupts the normal synthesis of methionine, which plays an important role in maintaining myelin sheath integrity, resulting in degeneration of the dorsal columns. This degeneration does not respond to classic treatment with vitamin B12 and folate supplementation, unlike SCD. Here, we describe a case of a 45-year-old woman with Philadelphia-positive B-cell acute lymphoblastic leukemia treated with hyperCVAD regimen with ponatinib, who after 14 doses of prophylactic IT MTX, developed progressive lower extremity weakness, paresthesias, gait instability, saddle anesthesia, and bowel/bladder dysfunction. Her neurologic exam was also notable for diffuse hyporeflexia. The onset of symptoms followed a diarrheal infection, and an initial MRI spine showed no evidence of abnormal enhancement. She was initially treated with intravenous immunoglobulins for presumed acute inflammatory demyelinating polyneuropathy. She then re-presented one week later with progressively worsening symptoms. A repeat MRI spine revealed a new longitudinally extensive T2 hyperintense signal within the dorsal columns from T7 to T12. CSF results were notable for mild pleocytosis and increased myelin basic protein; the latter of which is often seen in MTX-induced myelopathy. The patient received high-dose administration of key metabolites of the methyl-transfer pathway including S-adenosylmethionine (PO 400mg three times daily), folinate (IV 20mg four times daily), cyanocobalamin (PO 1000mcg once daily) and methionine (PO 5mg once daily) for 7 days. This treatment regimen resulted in both clinical and radiographic improvement. Subsequent MRI spine demonstrated complete resolution of the abnormal signal in the thoracic cord. This case highlights (1) the diagnostic complexity of IT MTX-induced myelopathy (2) the role response to treatment plays in uncovering this diagnosis, and (3) how the replacement of folate metabolites facilitates both radiographic and clinical improvement in IT MTX-induced myelopathy.

Diffuse Large B-cell Lymphoma of the Prostate: Case Study of an Uncommonly Encountered Entity

Abstract Introduction/Objective Hematologic neoplasms comprise less than 1% of prostate malignancies, with diffuse large b-cell lymphoma (DLBCL) accounting for 15% of those. Chronic lymphocytic leukemia/small lymphocytic lymphoma is most often seen, comprising 53% of lymphomas at this site, with the remainder consisting of marginal zone, mantle cell, and follicular lymphomas. Methods/Case Report Our case involves a 51-year-old African American male presenting to a medium-sized academic medical center with a chief complaint of hematuria with clot retention. Patient did endorse night sweats and chills at this time. Imaging revealed an 11 cm mass involving the prostate and bladder, a 10 cm right adrenal mass, and pelvic lymphadenopathy. A cystoscopy with transurethral resection was performed with tissue histology showing complete effacement of prostatic parenchyma by sheets of medium-sized, mildly irregular, non-cohesive cells with minimal cytoplasm. Tissue morphology appeared highly suspicious for lymphoma, but the rarity of this process along with the possibility of other lesions led to differential diagnoses including small cell carcinoma, poorly differentiated prostatic adenocarcinoma, high-grade urothelial carcinoma, and granulomatous prostatitis. Immunohistochemical staining of neoplastic cells showed CD20+ B cells with a non-germinal center immunophenotype (CD10-) and co-expression of Bcl-2 and c-myc. Subsequent FISH analysis demonstrated a Bcl-6 gene rearrangement without a Bcl-2 or MYC rearrangement. Ki67 was positive in 90% of tumor cells. Rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone was initiated for stage IV DLBCL with prophylactic intrathecal methotrexate. The patient has received 6 cycles of chemotherapy to date with resolution of the prostate and adrenal masses. Bladder involvement is still seen radiographically, but is suspected to be mainly necrotic tissue. Results (if a Case Study enter NA) N/A Conclusion Less aggressive lymphomas are more common, which makes this presentation additionally unexpected. We employed a wide battery of immunohistochemical stains, including NKX3.1, s100, gata-3, pan-ck, CD68, and chromogranin and synaptophysin, when initially evaluating the neoplastic tissue.

Response-Adapted Therapy in HIV-Associated Diffuse Large B-Cell Lymphoma: Updated Results of a Prospective Phase II Study of Short-Course-EPOCH-RR

Background: Response-adapted therapy aims to minimize toxicity while maintaining efficacy. Patients with HIV-associated lymphomas are at increased risk for complications and minimizing treatment is advantageous. In 33 patients with HIV-associated diffuse large B-cell lymphoma (DLBCL), we previously reported a 5-year freedom from progression (FFP) and overall survival (OS) rate of 84% and 68%, respectively, with 79% of patients receiving only 3 cycles of short course EPOCH-RR (Dunleavy, 2010). In that study, treatment duration was based on an interim FDG PET-CT scan comparing global reduction of SUV to baseline. Herein, we report an updated analysis including an additional 22 patients and investigate the predictive value of interim PET scans using modern Lugano response criteria. Methods: Eligible patients had untreated HIV-associated DLBCL with adequate organ function. All performance status and stages were eligible, including CNS involvement. Pre-treatment evaluation included bone marrow biopsy, lumbar puncture, CT and PET scan, and brain MRI/CT if indicated. Infusional EPOCH was delivered every 21 days with rituximab on days 1 and 5 (SC-EPOCH-RR) without dose-adjustment for a minimum of 3 and maximum of 6 cycles. HIV antiretroviral therapy (ART) was held until completion of systemic chemotherapy. Treatment response was determined by CT and PET imaging after 2 cycles, with restaging imaging performed consecutively after each cycle. Patients that had a global PET decrease > 50% compared to pre-treatment PET, were treated with only 1 additional cycle. Patients who did not decrease > 50% on PET, continued treatment until there was < 25% reduction in bidimensional products on serial CT imaging. Active CNS disease was treated with twice weekly intrathecal (IT) methotrexate until CSF clearance followed by maintenance IT therapy. All other patients received prophylactic IT methotrexate starting on cycle 3 for 8 doses. The primary endpoint of the study was progression-free survival (PFS). Independent and blinded review of PET scans using Lugano response criteria (Deauville score 1-3 = negative, score 4-5 = positive) was performed by a nuclear medicine specialist (M.A.). Results: Fifty-five patients were enrolled between March 2001 and February 2019. Median age was 42 (range, 9-60) and 85% were male. Ann Arbor stage was III/IV in 84% and 71% had a high-intermediate or high IPI score. Six (11%) patients had CNS involvement, and 6 (11%) had bone marrow involvement. Median CD4 count was 210 cell/m3 (range 0-1192). Cell-of-origin by Hans classified 69% as GCB and 22% were EBV positive. 31 patients were tested for MYC rearrangement by FISH and 5 (16%) were positive. Patients received a median of 3 cycles of therapy; 1 (2%) patient received only 1 cycle, 2 patients (4%) received 2 cycles, 45 patients (82%) received 3 cycles, 3 (5%) patients received 4 cycles, and 4 (7%) patients received 5 cycles. After a median potential follow-up of 12.6 years, 5-year FFP, PFS and OS were 76.0%, 64.3% and 71.8%, respectively [Figures 1, 2]. Two patients progressed during therapy, while 11 patients relapsed after therapy - all within 12 months of treatment completion. Of 18 deaths on study, 6 were due to disease progression and 12 died from causes unrelated to lymphoma or treatment. Of forty-seven patients with interim (post-cycle 2) PET scans, 30 (64%) became PET negative after 2 cycles. The 5-year PFS was not different in patients who achieved interim PET negativity: 73.4% versus 62.7% (p = 0.14 for comparison of entire PFS curves) [Figure 4]. Of the 13 total patients who progressed or relapsed, 5 were negative on interim PET. Conclusion:Response-adapted SC-EPOCH-RR therapy is effective for HIV-associated DLBCL and many patients are cured with only 3 cycles of therapy. Interim PET scans after 2 cycles using Lugano criteria did not reliably predict clinical outcomes. Further studies investigating the role of circulating tumor DNA (ctDNA) for genotyping and predicting clinical outcomes are planned. This work was supported by the Intramural Research Program of NCI. Disclosures Dunleavy: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees.

CNS relapse of diffuse large B cell Lymphoma A single centre experience.

Background and Objective:Central nervous system (CNS) relapse of diffuse large B cell lymphoma (DLBCL) is relatively uncommon and nearly fatal. Two years CNS relapse risk is 0.8% in low, 3.9% in intermediate and 12% in high risk patients. Our aim was to study, the baseline characteristics and outcome in term of median survival of DLBCL patients with CNS relapse.Methods:This is a retrospective analysis. All patients of DLBCL with CNS relapse from 2006 to 2014 were included. Data were collected from computerized Hospital Information System and analyzed for characteristics and median survival.Results:Out of twenty one patients included in the study, 14(66.3%) males and 7(33.7%) were females. On initial diagnosis of DLBCL, median age was 37.4 years (27-47). Ann Arbor stage of I-IV was in 3 (14.3%), 2(9.5%), 4(19%) and 12(57.1%) patients, respectively. Extra-nodal involvement was noted in 16(76.2%), high LDH in 18(85.7%), bone marrow involvement in 8(38.1%) and bulky disease in 5(23.8%) patients. International Prognostic Index (IPI) score was 1 in 4(19%), 2 in 9(42.9%), 3 in 8(38.1%) patients. Extra-nodal sites were gut in 2(9.1%) while 1(4.5%) patient of each of following organs involvement was seen: cervix, gluteal muscle, iliac bone, liver, ovaries, pancreas, parotid gland and testes. Chemotherapy CHOP was given to 16(76.2%) and RCHOP in 5(23.8%) patients. Prophylactic intrathecal methotrexate was given to 10(47.6%) patients. Complete response was in 10 (47.6%), partial response was in 3 (14.3%) and disease progression was in 8 (38.1%) patients. CNS relapse occurred in 17 (81%) patients within six months after completion of therapy. CNS relapse along with systemic disease was in 14(66.6%) patients. Isolated CNS relapse was noted in 7(33.3%) patients. Second line chemotherapy regimens were HDMTX 5(23.8%), HDMTX/TRIO IT 3(14.2%), HDMTX/HDAC 2(9.5%), HCVAD 3(14.2%), ICE 4(19.4%), DHAP 1(4.7%), ICE/HDMTX 1(4.7%), none 2(9.5%). Overall median survival of CNS relapsed patients was 54 days.Conclusion:Patients with DLBCL who had advanced stage, high LDH and extra-nodal involvement at initial presentation are at high risk for CNS relapse. About half of the patients had CNS relapse despite primary CNS prophylaxis. Once relapsed in CNS, these patients have very poor prognosis.

Rare Case of Patient with HIV Related Plasmablastic Lymphoma Presenting with Bilateral Parotid Involvement and Hypergammalobulemia

44 year old male with no past medical history presents with rapidly enlarging neck mass over past two months. He denied B-symptoms. Clinical examination revealed bulky midline neck mass with bilateral cervical and left supraclavicular adenopathy. 6/29/16 excisional lymph node biopsy of neck lymph node showed a monomorphic proliferation of malignant cells with large immunoblastic tumor cells with prominent nucleoli (Figure1). Neoplastic cells expressed MUM-1, CD138 (Figure 2), and were lambda light chain restricted. Neoplastic cells were negative for CD20, CD79, CD3, CD5, CD7, and BCL-2. Additionally, Cyclin D1, BCL-6, CD30, ALK-1, S100, CD56 was negative. Ki-67 was 99%. EBER by ISH was positive (Figure 3). Karyotype was normal. PET CT 7/1/16 Showed small hypermetabolic lymph nodes in the right neck, bilateral parotid gland with additional hypermetabolic activity in the left supraclavicular fossa and central neck base along with activity in the tongue base with maximum SUV 16.1. CT neck chest abdomen and pelvis 7/1/16 showed bilateral enhancing parotid lesions, large central midline neck mass with right strap muscle involvement. Also, there was soft tissue prominence of the adenoids, tonsil pillars, lingual tonsils, laryngeal ventricle. Last there was bilateral deep cervical, supraclavicular, & posterior cervical lymphadenopathy. Lumbar puncture, bone marrow biopsy, & MRI brain were negative for involvement. Labs 6/27/16: Platelet 126 10x3/µL, hemoglobin 15.7 g/dL, white blood cell 5.2 with variant lymphocytes. Uric acid 4.3 m/dL, total protein 9.3 g/dL, creatinine 1.23 m/dL, alanine aminotransferase 83 U/L, aspartate aminotransferase 83 U/L and complete metabolic panel otherwise normal. LDH 228 U/L, beta 2 microglobulin 4.5 mg/L. HIV-1 test was positive with 94316 copies/mL by PCR. CD4 count 65 cells/mcl. EBV VCA IgM <0.2 AI, EBV VCA IgG > 8.0 AI. IgG 3023 mg/dL, IgE 207IU/ML, IgA 581 m/dL, IgM 286 mg/dL, free kappa 117 mg/L, free lambda 97.94 mg/L and normal kappa/lambda ratio. SPEP with immunofixation consistent with inflammatory response. Peripheral blood flow cytometry revealed a minimal kappa predominant monoclonal B-cell population. Patient started on DA-EPOCH with prophylactic intrathecal methotrexate with excellent clinical response after first cycle. Plan for 4-6 cycles with prophylactic intrathecal chemotherapy followed by autologous stem cell transplantation. For supportive care, the patient was started on HAART therapy, acyclovir, fluconazole, Levaquin, azithromycin. To our knowledge this is the first case of bilateral parotid gland involvement in PBL. Furthermore it is unclear if the hypergammaglobulinemia is related to HIV infection vs. directly PBL related. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Transformation of Follicular Lymphoma to a High Grade B-Cell Lymphoma with MYC and BCL2 Translocations and Overlapping Features of Burkitt Lymphoma and Acute Lymphoblastic Leukemia

Most commonly, histologic transformation (HT) from follicular lymphoma (FL) manifests as a diffuse large B cell lymphoma, not otherwise specified (DLBCL, NOS). Less frequently, HT may result in a high-grade B cell lymphoma with MYC and BCL2 and/or BCL6 gene rearrangements, also known as "double-hit" or "triple-hit" lymphomas. In the 2016 revision of the WHO classification of lymphoid neoplasms, the category B-cell lymphoma, unclassifiable was eliminated due to its vague criteria and limiting diagnostic benefit. Instead, the WHO introduced the high-grade B-cell lymphoma (HGBL) category, characterized by MYC and BCL2 and/or BCL6 rearrangements. Cases that present as an intermediate phenotype of DLBCL and Burkitt lymphoma (BL) will fall within this HGBL category.Very rarely, HT results in both the intermediate DLBCL and BL phenotype, and exhibits lymphoblastic features, in which case the WHO recommends that this morphological appearance should be noted. In comparison to de-novo patients with DLBCL, NOS, those with MYC and BCL2 and/or BCL6 gene rearrangements have a worse prognosis.A 63-year-old female presented with left neck adenopathy. Lab assessment including complete blood count (CBC), complete metabolic panel (CMR), serum lactate dehydrogenase (LDH) and B-2 microglobulin were all normal. A whole body computerized tomography (CT) scan revealed diffuse adenopathy above and below the diaphragm. An excisional node biopsy showed grade 3A nodular FL. The Ki-67 labeling index was 40-50%. A bone marrow biopsy showed a small focus of para-trabecular CD20+ lymphoid aggregates.She received 6 cycles of bendamustine (90 mg/m2 days +1 and + 2) and rituximab (375 mg/m2 on day+2) with each cycle delivered every 4 weeks. A follow up CT scan at completion of therapy showed a partial response with resolution of axillary adenopathy and a dramatic shrinkage of the large retroperitoneal nodes.18 months later she had crampy abdominal pain in the absence of B symptoms. Positron emission tomography with 2-deoxy-2-[fluorine-18] fluoro- D-glucose integrated with CT (18F-FDG PET/CT) scan showed widespread adenopathy, diffuse splenic involvement and substantial marrow involvement. Biopsy of a 2.4 cm right axillary node (SUVmax of 16.1) showed involvement by grade 3A FL with a predominant nodular pattern of growth. A bone marrow biopsy once again showed only a small focus of FL.She received idelalisib (150 mg twice daily), and rituximab (375 mg/m2, monthly) beginning May, 2015. After 4 cycles, a repeat CT scan showed a complete radiographic response. Idelalisib was subsequently held while she received corticosteroids for immune-mediated colitis. A month later she restarted idelalisib with a 50% dose reduction. Two weeks later she returned to clinic complaining of bilateral hip and low lumbar discomfort but no B symptoms. A restaging 18F-FDG PET/CT in January of 2016 showed dramatic marrow uptake. A bone marrow aspirate showed sheets of tumor cells representing a spectrum from intermediate sized cells with lymphoblastic features to very large atypical cells with multiple nucleoli. Two distinct histologies were present; one remained consistent with the patient's known FL with a predominant nodular pattern and the other consistent with HT (The large atypical cells expressed PAX5, CD10, BCL2, and cMYC, and were negative for CD20, MPO, CD34, CD30, and BCL6). Focal areas showed faint, heterogeneous expression of terminal deoxynucleotidyl transferase (TdT) best seen on the clot section. Ki67 proliferation index was high (4+/4). FISH analysis showed two populations with MYC amplification and/or rearrangement, and no evidence of BCL6 rearrangement; a karyotype analysis showed a complex abnormal female karyotype with t (14; 18) and multiple structural and numerical abnormalities.She started dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-R-EPOCH) with concomitant prophylactic intrathecal methotrexate and cytarabine. She had but a short lived response before dying in hospice from progressive lymphoma.Whether idelalisib could provide a microenvironment for selection of more aggressive clones needs to be addressed. Our patient's clinical course is confounded by the incorporation of idelalisib while being further complicated by the complexity of HT and the mechanisms in which first-line chemotherapy regimens impact DHL. DisclosuresNo relevant conflicts of interest to declare.

Strict Treatment Regimen and Febrile Neutropenia Guidelines Allow Favorable Outcomes for Pediatric ALL in Southern India

Background: Children with Acute Lymphoblastic Leukemia (ALL) in resource-poor countries face major challenges including treatment abandonment and poor overall survival (OS) and event-free survival (EFS). To address these issues, in 2002 a non-profit pediatric hematology-oncology center was established in a tertiary medical institution in Kerala, India to provide high-quality treatment and supportive care at low cost. A standardized approach to pediatric leukemia care began in 2010. We present evidence that outcomes on par with that seen in resource-rich nations can be achieved with a rigorous treatment and supportive care approach.Methods: Following IRB approval, we reviewed clinical information and outcomes of all patients above 1 year and less than 14 years of age treated for newly diagnosed B- or T-ALL between January 1, 2010 and January 31, 2015. Seventy-six children were consecutively treated and all are included in this analysis. B-ALL patient treatment was stratified according to BFM relapse risk criteria with standard risk (SR) defined by age 1-6 yrs, peripheral WBC < 20 X 106/ul, good prednisolone response, absence of t(9:22) and t(4:11), and a day 33 marrow in remission by morphology. At any age, poor prednisolone response, t(9:22) or t(4:11), or day 33 marrow not in remission defined high risk (HR), and patients not meeting SR or HR criteria were intermediate risk (IR). Minimal residual disease assessment (MRD) was not utilized in risk stratification or treatment decisions. All patients were treated as per BFM 2002 with modifications. All patients received 4-drug (Vincristine/ Daunorubicin/ L Asparaginase/ Prednisolone) induction and Phase 2 induction of cyclophosphamide, cytosine arabinoside, and daily 6-mercaptopurine (6-MP), followed by consolidation with oral 6-MP and IV methotrexate (MTX), 2 gm/m2 x 4 for SR and IR B-ALL and 5 gm/m2 x 4 for HR B-ALL, T-ALL, and CNS disease. Phase 1 reinduction utilized adriamycin and dexamethasone. The Phase 2 reinduction regimen closely mirrored Phase 2 induction. HR B-ALL and T-ALL patients received 12 Gy prophylactic cranial irradiation, and those with CNS disease 18 Gy. Maintenance therapy consisted of daily oral 6-MP, weekly oral MTX, and monthly IV Vincristine and oral Dexamethasone for 104 weeks. Prophylactic intrathecal MTX was given 11 times through reinduction and every 3 months in maintenance. Febrile neutropenia protocols were enforced to ensure less than 30 minutes elapsed from presentation with fever > 38o C to initiation of broad spectrum antibiotics. To minimize sepsis risk, prophylactic GCSF was given between cycles to target ANC > 0.5 x 106/uL. OS and EFS were assessed by Kaplan-Meier method. Patients were censored at last follow-up. Abandonment was treated as an event in calculating EFS. Kuppuswami Socioeconomic Scale (KES) was applied using phone interviews of guardians.Results: Median follow-up time was 30.3 months (range, 1.9-61 months). One patient (1.3%) died during induction, 1 was censored at loss to follow-up upon transfer of treatment to another center, none abandoned treatment, and 6 (7.9%) relapsed, with 1 (1.3%) relapse within 90 days of diagnosis. At median follow-up, the OS was 93.4% and EFS 90.8% (95% CI, 81.1%-99.1%). SR accounted for 28 (36.8%), IR for 36 (47.4%), and HR for 11 (14.5%) patients. OS by risk stratification is shown in Figure 1. KES analysis on the 65 contactable families revealed a median family income between Indian Rs. 14,000-37,000 (US $218-577)/month, and 14 (21.5%) having income less than Rs. 9,300 (US $145)/month. Thirty (46.1%) stratified as lower-middle class or lower. The primary wage earner had less than a high school education in 21 (32.3%), and was at a clerical or lower work level in 46 (70.8%) of families.Conclusion: Our data demonstrate that, for pediatric ALL, results similar to resource-rich countries can be provided in resource-poor areas through a tertiary care center maintaining adherence to globally accepted guidelines for treatment and management of treatment-associated complications. We plan to report minimum 5-year follow-up for all patients in future. Future prospective studies will examine the role of MRD-based stratification and allogeneic transplant options for high-risk patients, as well as seek to extend the low rates of toxic death and abandonment to neighboring centers by implementation of best practices throughout the region. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Treatment Outcomes in Relapsed/Refractory Adult T-Cell Lymphoma/Leukemia and Role of CNS Prophylaxis: A New York City Hospital Experience

Background:Adult T-cell leukemia/lymphoma (ATLL) is a rare and aggressive peripheral T-cell neoplasm characterized by clonal human T-cell lymphotropic virus type-1 (HTLV-1) proviral DNA integration with host T lymphocytes.It presents as aggressive (acute/lymphomatous) or indolent (chronic/smouldering) subtypes. The aggressive subtypes have median survival of 6-13 months despite aggressive chemotherapy regimens. Presently, there is no established therapy for patients with relapsed/refractory disease. The data on efficacy of traditional chemotherapy agents in this setting is scant. In the last 6 years, 4 new drugs have been approved by US Food and Drug Administration for patients with relapsed/refractory peripheral T cell lymphoma (PTCL): pralatrexate and 3 histone deacetylase (HDAC) inhibitors (romidepsin, belinostat, vorinostat). Treatment approaches for PTCL are often applied to ATLL, as there is little data available for this subtype. However, none of the HDAC inhibitor trials included ATLL patients and there was only one patient in the pivotal PROPEL study for pralatrexate. The prevalence of CNS disease in the aggressive subtypes varies from 3 to 50 % and the efficacy of intrathecal chemotherapy is not known.Methods:To investigate the therapeutic benefit of second-line therapy and prophylactic intrathecal therapy, we reviewed all patients with ATLL at King's County Hospital between 2006 and 2014. Individual chart review was performed to report clinicopathologic features and treatment outcomes. SPSS was used for statistical analysis.Results:Fifty five patients were identified between January 2006 and December 2013 including 33 (60%) females and 22 (40.0%) males with a median age of 54 years (range, 31-78 years). All patients had immigrated to the United States from the Caribbean or South America. Median follow-up period was 6.6 months (0.4-124). Forty four patients were dead, 5 were alive and 6 were lost to follow-up at the time of analysis. Stage distribution was 26%, 51%, 16%, 6% for stage I, II, III and IV respectively. Forty three patients (78.2%) received etoposide/prednisone/vincristine/cisplatin/adriamycin (EPOCH) for first-line therapy. Twenty nine patients received second-line chemotherapy: gemcitabine/oxaliplatin, iphosphamide/cisplatin/etoposide (ICE), romidepsin, pralatrexate and high dose methotrexate. Median progression free survival was 6.8 weeks (range 1.6-72). No complete responses were seen. Partial response was seen in 9 (n=29) patients (31%). Median duration of response was 20.8 weeks (range 9.1-40). Three (5%) patients had CNS involvement at presentation. Prophylactic intrathecal therapy with methotrexate (IT MTx) 12 mg Q14 days was given to 21 patients (40.3%). CNS relapse was seen in 3 (14.2%) patients who received IT MTx and 6 (19.4%) patients who did not receive intrathecal chemotherapy. All patients with CNS relapse also had peripheral relapse.Conclusion:ATLL is a rare and difficult disease to manage. In our experience of relapsed/refractory ATLL, patients appear to have modest response rate to a second-line chemotherapy and these responses are not long lasting. In our patient population, risk of CNS disease at presentation was low (5%) but the incidence approaches 17.3% at the time of relapse. Administration of prophylactic intrathecal methotrexate showed a trend towards reducing the incidence of CNS disease although the results were not statistically significant. DisclosuresNo relevant conflicts of interest to declare.

Methotrexate-induced chemical meningitis in patients with acute lymphoblastic leukemia/lymphoma.

Background:Intrathecal methotrexate (ITMTX) is an important component in the treatment as well as prophylaxis of leukemia/lymphoma. ITMTX can cause chemical meningitis characterized by vomiting, headache, and fever lasting 2-5 days with spontaneous resolution of symptoms which differentiates this syndrome from bacterial meningitis.Objective:This prospective observational study was carried out to determine incidence of post-ITMTX syndrome in patients receiving prophylactic ITMTX as part of Berlin-Frankfurt-Munster (BFM) protocol.Materials and Methods:Patients aged 15-50 years receiving BFM 90 or BFM 95 protocol for acute lymphoblastic leukemia or lymphoblastic lymphoma were followed up for post-ITMTX syndrome, defined as vomiting, headache and fever between 38° and 39°C following ITMTX.Results:Thirty-three patients received a total of 297 courses of ITMTX. Of the 297 doses of ITMTX, 20 episodes (6.7%) of post-ITMTX syndrome were observed. The incidence of post-ITMTX syndrome was highest after the second dose of ITMTX (24%). The most common symptom of post-ITMTX syndrome was headache which was seen in 17 (85%) patients. Seventeen (85%) patients had vomiting, 10 (50%) patients had fever, and 4 (20%) patients had backache. Meningeal signs were present in 2 (10%) patients.Conclusions:Post-ITMTX syndrome is not uncommon in adult patients receiving prophylactic ITMTX for treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma. Patients develop a toxic syndrome closely mimicking acute bacterial meningitis but spontaneous recovery is seen without any neurological sequelae.

Isolated Ocular Manifestation of Relapsed Chronic Myelogenous Leukemia Presenting as Myeloid Blast Crisis in a Patient on Imatinib Therapy: A Case Report and Review of the Literature.

Blast phase in chronic myelogenous leukemia (CML) has rarely been reported to involve extramedullary sites like skin, lymph nodes, and central nervous system. Clinical history, characteristic hematologic findings (elevated leukocyte counts, myelocytic predominance, and basophilia), and Philadelphia chromosome are of high diagnostic significance especially in isolated extramedullary presentations. We describe a unique case of CML relapse with blast phase involving the eye. A 66-year-old man with a known diagnosis of CML on imatinib and in molecular remission for 3 years presented with a painful blind eye. Histologic examination revealed diffuse involvement of choroid, iris, vitreous humor, and the optic nerve by blast cells. The blasts expressed CD34, aberrant TdT, and a myeloid phenotype (CD13, CD33, and CD117). Fluorescence in situ hybridization (FISH) of vitreous fluid detected BCR-ABL1 gene rearrangement. Additionally, trisomy 8 and gains of 9 and 22 were seen which were not present in the initial diagnostic marrow study 3 years ago. At relapse, the bone marrow, peripheral blood, and the cerebrospinal fluid were not involved by CML. Patient received induction chemotherapy and single dose prophylactic intrathecal methotrexate and was maintained on antityrosine kinase therapy and eventually underwent allogenic stem cell transplantation.

Mucoepidermoid Carcinoma of the Parotid Gland in Childhood Survivor of Acute Lymphoblastic Leukemia With Need of Radiotherapy for Treatment and Review of the Literature

Diagnosis of secondary malignancies began with the increasing survival in childhood cancer. Children treated for acute lymphoblastic leukemia (ALL) have an increased risk for developing mucoepidermoid carcinoma (MEC) of the parotid gland. The latent period ranges from 5 to 16 years. A 2 6/12-year-old girl was treated for pro-B ALL. Treatment included multidrug chemotherapy, prophylactic intrathecal methotrexate, and cranial radiotherapy. MEC of the left parotid gland was diagnosed at the age of 8 years, 3 years after completing treatment. She was treated with multiple surgery and radiotherapy. The authors aimed to emphasize the need for concern about second cancers of the parotid gland in children treated for ALL.

A unifying diagnosis for pancytopenia, fever, hypoglycemia, and lactic acidosis

A unifying diagnosis for pancytopenia, fever, hypoglycemia, and lactic acidosis

Persistent cognitive deficits, induced by intrathecal methotrexate, are associated with elevated CSF concentrations of excitotoxic glutamate analogs and can be reversed by an NMDA antagonist

For patients with acute lymphoblastic leukemia or non-Hodgkin lymphoma, intrathecal (IT) methotrexate (MTX) significantly reduces the risk of relapse within the central nervous system, but is associated with neurotoxic sequelae. We established a rat model of MTX-induced cognitive deficits to further investigate the underlying pathophysiology and to develop protective therapeutic interventions. IT MTX 0.5 mg/kg was administered to 10-week old male Long Evans rats. Cerebrospinal fluid (CSF) was collected for measurement of folate, homocysteine, and excitotoxic glutamate analogs. Recognition and spatial memory were tested in the novel object recognition (NOR) task and the object placement (OP) task, respectively. Four doses of IT MTX in a two-week period induced cognitive deficits persisting at least three months after the final injection. CSF concentrations of the excitotoxic glutamate analogs homocysteic acid and homocysteine sulfinic acid were increased relative to baseline for the same three-month period. Dextromethorphan, a noncompetitive antagonist at the N-methyl- d-aspartate receptor, administered at a dose of 2 mg/kg intraperitoneally twice daily for a total of four doses, improved cognitive function among the MTX-treated rats, with no effect on control rats. Although this improvement was transient, each repeated treatment with dextromethorphan was followed by normalization of cognitive function. In conclusion, IT MTX induces persistent alterations in glutaminergic tone that may contribute to persistent cognitive deficits. Treatment with a glutamate receptor antagonist such as dextromethorphan may ameliorate the negative cognitive outcomes observed among patients with leukemia or lymphoma treated with repeated doses of prophylactic IT MTX.

Adult anaplastic large cell lymphoma involving the central nervous system: a rare clinical scenario

Dear Editor, Anaplastic large cell lymphoma (ALCL) is a rare T-cell non-Hodgkin lymphoma with distinct pathologic features characterized by CD30 expressing large pleomorphic lymphoid cells with or without anaplastic lymphoma kinase (ALK) gene rearrangement. The disease commonly spreads to bone marrow, skin, lung, liver, and, rarely, other sites [1]. ALCL rarely occurs in the central nervous system (CNS), of which most are primary ALCL reported in pediatric or immunocompromised patients [2]. ALCL with secondary CNS involvement is extremely rare [3]. Here, we present two adult patients having ALCL with secondary CNS involvement, both treated with standard chemotherapy and autologous hematopoietic stem cell transplant (auto-SCT), and both patients had a relatively long survival. To date, only three other similar cases have been reported and all had much shorter survival with no auto-SCT treatment. A 27-year-old man who presented with a mediastinal mass and general lymphoadenopathy was subsequently diagnosed with ALK-positive ALCL. The tumor cells expressed CD30 and ALK. He received cyclophosphamide, hydroxydaunorubicin (doxorubicin), Oncovin (vincristine), and prednisone/prednisolone (CHOP) chemotherapy along with prophylactic high-dose intrathecal methotrexate for three cycles. One year after the initial diagnosis of ALCL, the patient developed seizures. Contrast-enhanced brain MRI revealed diffuse edema in both the parietal and occipital regions. There was also evidence of parenchymal disease both above and below the tentorium in addition to diffuse pial enhancement and dural involvement (Fig. 1a and b). Cerebrospinal fluid (CSF) cytospin examination revealed a population of large anaplastic lymphoid cells in the background of few granulocytes and macrophages. Flow cytometry of the CSF identified abnormal T cells expressing CD30 and CD4 with loss of other pan-T-cell markers (CD3, CD5, and CD7). A T-cell gene rearrangement analysis of the CSF DNA sample detected a prominent but dim T-cell receptor gamma monoclonal peak. No circulating lymphoma cells were identified in the peripheral blood at that time point. The patient received intrathecal methotrexate and cytarabine followed by wholebrain radiation. His disease was well controlled although it was complicated with severe encephalopathy and cerebral infarct, which caused peripheral vision loss. Five years later, he developed severe abdominal pain and diarrhea. PET/CT scan revealed hypermetabolic activity in the distal duodenum, and biopsy was consistent with recurrent ALCL X. Zhang Department of Pathology and Cell Biology, University of South Florida College of Medicine, Tampa, FL, USA

Intrathecal methotrexate induces focal cognitive deficits and increases cerebrospinal fluid homocysteine

Although most children with acute lymphoblastic leukemia (ALL) can be cured, a significant subset of survivors manifests focal deficits in cognitive function, even when the treatment regimen does not include cranial radiation. Intrathecal administration of the folate antagonist methotrexate (MTX) is necessary to prevent leukemic relapse within the central nervous system, but is suspected to contribute to treatment-induced cognitive dysfunction. To better elucidate the underlying pathophysiology, we sought to establish a rodent model of the cognitive and neurotoxic effects resulting from direct administration of MTX into the cerebrospinal fluid (CSF). MTX or artificial CSF was injected via transcutaneous puncture at the level of the cisterna magna. Subsequent behavioral tests were designed to assess cognitive domains frequently impaired among children treated for ALL. MTX administration produced both recognition and spatial memory deficits, without altering general activity or motor coordination. In addition, MTX significantly reduced folate levels in both CSF and serum and increased CSF homocysteine. Thus, we have established an animal model that mimics the clinical effects of prophylactic intrathecal MTX on cognitive function. Using this model we can further study the pathophysiology of MTX-induced cognitive dysfunction and test protective interventions.

High-Dose Methotrexate and Azidothymidine in Combination with Alternating DA-EPOCH Is An Effective Regimen for the Treatment of EBV-Related Plasmablastic Lymphoma.

Abstract 4753 IntroductionPlasmablastic lymphoma (PBL) is an aggressive and generally fatal, rare type of B-cell non-Hodgkin's lymphoma (NHL) with predilection to sino-oral mucosa. PBL is usually associated with human immunodeficiency virus (HIV) and displays an unusual phenotype lacking the expression of B-cell surface antigens. PBLs are infected by Epstein Barr virus (EBV) in approximately 80% of cases and exhibit a restricted pattern of EBV gene expression as they do not typically express latent membrane proteins (LMPs), which enforce viral latency. Azidothymidine (AZT), a thymidine analogue, is an excellent substrate for EBV thymidine kinase, and is capable of inducing EBV lytic gene expression and apoptosis in primary Type I latency EBV+ Burkitt lymphoma (BL) cell lines. AZT was initially developed as an antineoplastic agent but was found to have low efficacy due to poor affinity to human DNA polymerase and low incorporation into DNA. The chemotherapy drug methotrexate (MTX), which also induces gamma-herpes virus lytic induction, inhibits thymidylate synthase thus blocking de novo synthesis of dTMP increasing the likelihood of AZT incorporation into DNA. Indeed, the combination of high-dose MTX and AZT was found to be clinically efficacious in HIV-infected patients with aggressive relapsed NHL. Similarly, at the University of Miami, we have found this drug combination to be highly effective when used in patients with aggressive gamma-herpes virus lymphomas including EBV+ BL and human herpes virus 8 (HHV-8) related primary effusion lymphoma (solid PEL). We report here the role of high dose MTX plus intravenous AZT with alternating infusional EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and adriamycin) in the treatment of HIV associated EBV+ plasmablastic lymphoma. MethodsThree HIV+ patients with biopsy proven, EBV-encoded RNA (EBER)+ PBL in sino-oral mucosa were treated with high dose methotrexate (4.5 g/m2 IV on day 1) and AZT 1.5 g IV infusion q12 hours (days 1-3) alternating with dose-adjusted (DA) EPOCH chemotherapy for 6-8 cycles as first line therapy. Patients were started/kept on HAART and were administered prophylactic intrathecal MTX±cytarabine. Responses were evaluated by oral exam and CT scans. ResultsSelected characteristics of patients are demonstrated in Table. Only Patient 2 was on HAART at the time of diagnosis. Patient 1 had intracranial extension of the large left maxillary lesion through sphenoid sinus with negative CSF cytology. All patients treated with HD-MTX/AZT and alternating EPOCH as above achieved a complete remission (CR). Patient 1 achieved CR after the 3rd cycle. However, 19 days after the 4th cycle he was found to have local recurrence, which was thought to be secondary to poor chemotherapy penetration to necrotic oral palate tissue, and was administered a total of 4620 cGy intensity-modulated radiotherapy to head and neck region followed by consolidation with the same chemotherapy regimen for 4 more cycles. He remains alive and free of disease after 14 months. Patient 2 and 3 received a total of 6 cycles of chemotherapy and remain disease-free after 12 and 13 months, respectively. No grade ≥3 toxicities were encountered during the treatment. ConclusionThe combination of high dose MTX and AZT plus alternating DA-EPOCH chemotherapy is a tolerable and effective treatment for HIV related EBV+ plasmablastic lymphomas. The combination of MTX and AZT is a highly active, EBV lytic inducing and targeted regimen which deserves further investigation in the treatment of gamma-herpes virus associated malignancies.NoSexAge at dxCD4 at dxLDH (normal<618)Stage# of cyclesDFS (from dx)1M52571300IIB4 + IMRT + 4>14 mos2F33102638IIA6>12 mos3M44339450IIA6>13mos Disclosures:No relevant conflicts of interest to declare.

Patterns of Outcome Following Recurrence in Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Long Follow-up From a Single Centre.

Abstract 2921Poster Board II-897 Background:Despite improvements in outcome of patients (pts.) with DLBCL, the prognosis for those who relapse after first-line treatment remains very poor. This retrospective analysis reports outcome of pts. with DLBCL treated before the routine use of Rituximab, with a median (med.) follow-up of 12 years. Patients and Methods:Between 1985 and 2003, 461 pts. were diagnosed with DLBCL at SBH. 384/461 (83%, male: 208, med. age: 60 years, range 17-95) were treated with curative intent (CI) and form the basis of this analysis. Those with primary CNS or primary mediastinal B-cell lymphoma and HIV +ve pts. were excluded. Histology at diagnosis included 31 pts. with ‘composite' lymphoma (29 follicular [FL], 1 lymphoplasmacytic, 1 ‘MALT') and 17 with ‘discordant' lymphoma (all FL).The majority, 142 (37%), had Stage IV disease, 99 (26%) stage I, 88 (23%) stage II and 55 (14%) stage III. The IPI score (ascribed retrospectively) was low-risk in 189 (49%), low-intermediate (int.) in 110 (29%), high-int. in 64 (17%) and high-risk in 21 (5%). 354/384 (92%) received an anthracycline-containing regimen, according to protocols in use at the time. 30 pts. (8%) with localised disease received radiotherapy alone. Prior to 2001, all pts. received prophylactic intra-thecal methotrexate; subsequently, only those at high risk for CNS relapse did so. Results:CR/CRu was achieved in 240/384 pts. (63%) and PR in 67 (17%). 53 (14%) did not respond (NR) and 24 (6%) died of causes related to initial therapy. Overall survival (OS) correlated with outcome to therapy (CR/CRu vs PR vs NR, p<0.0001). The med. overall (OS) and cause-specific survival were 6 and 12 years respectively. The med. remission duration (RD) has not been reached, after a med. follow-up for living pts. of 12 years (range 2-24). On univariate analysis, age, stage and IPI score at diagnosis correlated with both survival (p=0.0006, <0.0001, <0.0001) and RD (p=0.02, 0.02, 0.008) respectively. 92 of the 240 pts. (38%) in whom CR/CRu was achieved relapsed at a med. of 10 months; none in the CNS. 82/92 pts. (89%) had a repeat biopsy at recurrence which in 6 revealed FL and in 1 ‘MALT' lymphoma. In 14 pts. recurrence of DLBCL occurred after 5 years. The med. age at relapse was 65 years. Stage and IPI score were assessable in 80/85 pts. with ‘pure' DLBCL at relapse, namely: Stage I:26 pts. (31%), II:10 (12%), III:19 (22%), IV:25 (29%). 46% of pts. who relapsed with Stage I disease had Stage I at presentation and 72% who relapsed with Stage IV had the same stage at diagnosis. IPI scores at recurrence were: low-risk:42 (49%), low-int:25 (29%), high-int:9 (11%), and high-risk:4 (5%). 66/85 pts. (78%) received further treatment with CI, 2nd CR/CRu being achieved in 36/66 (55%; 36/85 if all pts. with recurrent DLBCL are considered), and PR in 14 (21%). 16 pts. had NR (only 1 of them responded to subsequent alternative therapies). OS from recurrence (med. for all pts.= 22 months) correlated with outcome to ‘salvage' therapy (CR/CRu vs PR vs NR, p<0.0001). The med. 2nd RD was 3 years. Amongst the 45 pts. aged '60 years at relapse and thus eligible for high-dose treatment (HDT) with autologous haematopoietic stem cell support, 19 (16 in CR/CRu and 3 in PR; med. age, 46 years) went on to receive it but only 5 of the latter are alive at last follow-up, 13 (including the 3 pts. treated in PR) having died of lymphoma (9) or treatment-related causes (4). The reasons for not proceeding to HDT (in 21 pts. achieving a 2nd CR) were: age (8), comorbidity (4), early recurrence (2) failure to mobilise cells (2), toxicity of prior therapy (3) and pt. choice (2). On univariate analysis, survival from recurrence correlated only with the IPI score at recurrence (p=0.009). Overall, 65% of pts. who developed recurrent disease died of lymphoma (including 28/30 pts. in whom 2nd CR/CRu was not achieved with the first ‘salvage' therapy). Thus, only 12/85 pts. with recurrent disease are currently alive, 3 have been lost to follow-up. Conclusion:Despite the curative potential of HDT, these data confirm that recurrence of DLBCL, in an unselected patient population, carries an appalling prognosis. Improving initial therapy is therefore crucial. In pts. in whom conventional 2nd-line therapy has failed, it is entirely justifiable to evaluate experimental therapies. Disclosures:No relevant conflicts of interest to declare.

Central nervous system occurrence in elderly patients with aggressive lymphoma and a long-term follow-up

Secondary central nervous system (CNS) involvement by aggressive lymphoma is a well-known and dreadful clinical complication. The incidence and risk factors for CNS manifestation were studied in a large cohort of elderly (>60 years) patients with aggressive lymphoma. In all, 444 previously untreated patients were randomized to receive 3-weekly combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone or cyclophosphamide, mitoxantrone, vincristine and prednisone (CNOP) (doxorubicin substituted by mitoxantrone) chemotherapy with or without filgrastim. Prophylactic intrathecal methotrexate was given to patients with lymphoma involvement of bone marrow, testis and CNS near sites. In all 29 of 444 (6.5%) developed CNS disease after a median observation time of 115 months. CNS was the only site of progression/relapse in 13 patients while part of a systemic disease manifestation in 16 patients. In univariate risk factor analysis, CNS occurrence was associated with extranodal involvement of testis (P = 0.002), advanced clinical stage (P = 0.005) and increased age-adjusted International Prognostic Index score (aaIPI; P = 0.035). In multivariate analysis, initial involvement of testis remained significant and clinical stage was of borderline significance. The median survival time was 2 months after presentation of CNS disease. A significant proportion of elderly patients with advanced aggressive lymphoma will develop CNS disease. CNS occurrence is related to testis involvement, advanced clinical stage and high aaIPI and the prognosis is dismal.

Prospective Management of Primary Testicular Lymphoma (PTL) with Doxorubicin-Based Chemotherapy, Prophylactic Intrathecal (IT) Methotrexate and Radiotherapy (RT), but without Rituximab: Results from IELSG.

Introduction: PTL is a rare extranodal lymphoma characterized by a continuous pattern of systemic relapses in spite of doxorubicin-based therapy. There are also frequent relapses in the contralateral testis and the central nervous system (CNS). Therefore we decided to determine whether prophylaxis of the CNS and the contralateral testis would modify the pattern of relapse of PTL.Patients and methods: From 1993 to February 2002 in IELSG member institutions patients with PTL (presenting with testicular enlargement) were managed with doxorubicin-based therapy according to institutional policy, with the addition of four doses of IT methotrexate (15 mg) during the first 6 weeks. At the end of chemotherapy scrotal RT (30 Gy) was given to all patients and 30–36 Gy nodal RT to those with stage II disease. Rituximab was not used in this cohort because it was not yet generally available for patients with diffuse large B-cell lymphoma.Results: There were twenty seven patients; two refused chemotherapy and/or RT/IT therapy and one RT, leaving 24 eligible for analysis. Median age was 60 years (range 31–80). Ann Arbor stage was I in 17, II in four, and four in three patients. B-symptoms were present in one patient. The right testis was involved in 13 and the left in 11 patients. Serum LDH was elevated in four of 21 with available values. No patient had CNS involvement at diagnosis. Pathology was diffuse large B-cell lymphoma in all patients. Treatment was CHOP in 21, alternating triple therapy in two, and hyper-CVAD in one patient. Three patients died during therapy: one from neutropenic sepsis and two from toxicity of systemic methotrexate. The remaining 21 patients achieved a complete remission. With a median follow-up of 57 months (range 8–123) for survivors, seven patients have relapsed, three in the CNS. There were no testicular relapses. Eight patients have died: three from toxicity during induction, three from relapsed lymphoma, one from gastric carcinoma and one from sudden death, both in complete remission. At 5 years the projected progression-free survival was 78%, and survival 66%, but both without an apparent plateau. Freedom from progression in the CNS was 84%, with a plateau.Conclusions: Patients with PTL treated prospectively with doxorubicin-based therapy before the availability of rituximab exhibit the continuous pattern of relapse previously reported. Scrotal RT seems eliminate testicular relapses, and prophylactic IT methotrexate seems to reduce, but not eliminated CNS relapses. These need to be confirmed by longer follow-up. The ongoing IELSG-10 should determine whether the addition of rituximab alters the continuous pattern of systemic relapses. Future studies should determine the molecular basis of the continuous relapses and minimize both systemic and CNS relapses.

Glioblastoma multiforme occurring in a child with acute lymphoblastic leukemia

A three and a half year old boy was diagnosed to have acute lymphoblastic leukemia in September 2002 and was treated with induction chemotherapy. He also received prophylactic cranial irradiation (12 Gy) and intrathecal methotrexate. In November 2005, at the age of 7 years, he developed right focal seizures and was diagnosed to have a glioblastoma in the left parietooccipital region while the leukemia was in remission. The possibilities are the glioma may have been radiation- and / or chemotherapy-induced.