Intermediate-dose cytarabine is an effective therapy for adults with non-Langerhans cell histiocytosis

Background Non-Langerhans cell histiocytosis, including Erdheim–Chester disease (ECD), Rosai–Dorfman disease (RDD), indeterminate cell histiocytosis (ICH), and unclassified histiocytosis, is a rare disorder lacking a standard treatment strategy. We report our experience using intermediate-dose cytarabine as the first or subsequent therapy in non-Langerhans cell histiocytosis. Results Eight ECD patients, 5 RDD patients, 1 ICH patient and 1 unclassified histiocytosis patient were enrolled. Intermediate-dose cytarabine therapy was administered as 0.5-1.0 mg/m2 of intravenous cytarabine every 12 hours for 3 days every 5 weeks. The median age at cytarabine initiation was 45 years (range, 18–70 years). The median number of cycles of cytarabine administered was 6 (range, 2–6). The overall response rate (ORR) was 86.7% in the overall cohort, including 6.7% with complete response and 80.0% with partial response. All patients (n=10) with CNS involvement achieved disease improvements. One patient experienced disease recurrence 19 months after cytarabine therapy. The median follow-up duration for the entire cohort was 12 months (range, 4-61 months). The 1-year progression-free survival (PFS) and overall survival (OS) rates were 85.6% and 92.3%, respectively. The most common toxicity was haematological adverse events, including grade 4 neutropenia and grade 3-4 thrombocytopenia. No treatment-related deaths occurred. Conclusions Intermediate-dose cytarabine is a cost-effective treatment option for non-Langerhans cell histiocytosis patients, especially for those with CNS involvement.

Successful BCMA CAR-T Therapy for Multiple Myeloma With Central Nervous System Involvement Manifesting as Cauda Equina Syndrome—A Wandering Road to Remission

Multiple myeloma (MM) with central nervous system (CNS) involvement is rare with only 1% incidence. So far, there is no standard or effective treatment for CNS MM, and the expected survival time is fewer than 6 months. Here, we report a case of MM with CNS involvement presented with cauda equina syndrome (CES) who achieved complete remission after anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T (CAR-T) cell therapy (Chictr.org.cn, ChiCTR1800017404). The expansion of BCMA CAR-T cells was observed in both peripheral blood (PB) and cerebrospinal fluid (CSF). The CAR-T cells peaked at 2.4 × 106/l in CSF at day 8 and 4.1 × 109/l in PB at day 13. The peak concentration of interleukin (IL)-6 in CSF was detected 3 days earlier, and almost five times higher than that in PB. Next, morphological analysis confirmed the elimination of nucleated cells in CSF 1 month after CAR-T cell treatment from 300 cells/μl, and the patient achieved functional recovery with regressed lesion shown in PET-CT. The case demonstrated that BCMA CAR-T cells are effective and safe in this patient population.

Focal Seizures and Posterior Reversible Encephalopathy Syndrome as Presenting Signs of IgA Vasculitis/Henoch-Schoenlein Purpura—An Educative Case and Systematic Review of the Literature

Background: IgA vasculitis/Henoch-Schoenlein purpura (IgAV/HSP) is a systemic small vessel vasculitis of unknown pathogenesis predominantly affecting children. While skin, GI tract, joints, and kidneys are frequently affected and considered, central nervous system (CNS) involvement of this disease is underestimated.Methods: We provide a case report and systematically review the literature on IgAV, collecting data on the spectrum of neurological manifestations.Results: We report on a 7-year-old girl with IgAV who presented with diplopia and afebrile focal seizures, which preceded the onset of purpura. Cranial magnetic resonance imaging was consistent with posterior reversible encephalopathy syndrome (PRES), showing typical focal bilateral parietal swelling and cortical and subcortical high signal intensities on T2-fluid attenuated inversion recovery (FLAIR) images predominantly without diffusion restriction. Cerebrospinal fluid analysis and blood tests excluded systemic inflammation or vasculitis. Interestingly, hypertension was not a hallmark of the developing disease in the initial phase of PRES manifestation. Renal disease and other secondary causes for PRES were also excluded. Supportive- and steroid treatment resulted in restitution ad integrum. Reviewing the literature, we identified 28 other cases of IgAV with CNS involvement. Severe CNS involvement includes seizures, cerebral edema, or hemorrhage, as well as PRES. Thirteen patients fulfilled all diagnostic criteria of PRES. The mean age was 11.2 years (median 8.0, range 5-42 years), with no reported bias toward gender or ethnic background. Treatment regimens varied from watchful waiting to oral and intravenously steroids up to plasmapheresis. Three cases showed permanent CNS impairment.Conclusion: Collectively, our data demonstrate that (I) severe CNS involvement such as PRES is an underappreciated feature of IgAV, (II) CNS symptoms may precede other features of IgAV, (III) PRES can occur in IgAV, and differentiation from CNS vasculitis is challenging, (IV) pathogenesis of PRES in the context of IgAV remains elusive, which hampers treatment decisions. We, therefore, conclude that clinical awareness and the collection of structured data are necessary to elucidate the pathophysiological connection of IgAV and PRES.

Distinguishing Between Multisystem Inflammatory Syndrome, Associated With COVID-19 in Children and the Kawasaki Disease: Development of Preliminary Criteria Based on the Data of the Retrospective Multicenter Cohort Study

Objectives: Diagnostic between multisystem inflammatory syndrome associated with COVID-19 in children (MIS-C) and Kawasaki disease (KD) can make difficulties due to many similarities. Our study aimed to create a Kawasaki/MIS-C differentiation score (KMDscore) allowing discrimination of MIS-C and KD.Study design: The retrospective multicenter cohort study included clinical, laboratory, and instrumental information about MIS-C (n = 72) and KD (n = 147). The variables allowed to discriminate both conditions used to construct and validate the diagnostic score called the KMDscore.Results: Patients with MIS-C were older, had earlier admission to the hospital, had a shorter time before fever resolution, two times frequently had signs of GI and CNS involvement observed, and had more impressive thrombocytopenia, higher level of CRP, ferritin, ALT, AST, LDH, creatinine, triglycerides, troponin, and D-dimer compared to KD patients. Respiratory signs in MIS-C were presented with pleuritis, acute respiratory distress syndrome, oxygen dependency, lung infiltration, and ground-glass opacities in CT. The heart involvement with fast progression of myocarditis provided the severity of MIS-C and ICU admission due to 12 times higher arterial hypotension or shock and required cardiotonic. No differences in the frequency of CA lesions were seen in the majority of cases. Five criteria, CRP >11 mg/dl (18 points), D-dimer >607 ng/ml (27 points), age >5 years (30 points), thrombocytopenia (25 points), and GI involvement (28 points), were included in the KMDscore. The summa >55 points allowed to discriminate MIS-C from KD with a sensitivity of 87.5% and specificity of 89.1%.Conclusion: The KMDscore can be used to differentiate the diagnostic of MIS-C from KD.

Central Nervous System Involvement By Mantle Cell Lymphoma

Background: While extranodal involvement by mantle cell lymphoma (MCL) is relatively common, involvement of the central nervous system (CNS) is rare (<5% of cases), with limited treatment options. We report the outcomes of 36 patients (pts) with CNS involvement compared to 72 matched control MCL pts without CNS involvement. Methods: MCL pts with CNS involvement seen at Mayo Clinic between 1/1995-9/2020 were identified using the Mayo Data Explorer tool. CNS involvement was defined by tissue biopsy confirmed CNS MCL, CSF analysis demonstrating lymphoma cells, and/or neuroimaging findings compatible with CNS involvement. A 2:1 control group of MCL pts without CNS involvement, matched by age (+/- 2 years) and year of diagnosis (+/- 1 year), was selected among all MCL cases. Medical records were reviewed for baseline characteristics, treatment modalities, and outcomes. Kaplan-Meier method was used for time to event analysis. Wilcoxon test was used to compare continuous variables and Chi square test was used for categorical variables. Results: Out of 1,753 pts with MCL, 36 (2%) had evidence of CNS involvement, including 4 pts with CNS involvement at initial MCL diagnosis. Baseline characteristics of pts with CNS involvement (CNS MCL group) and those without CNS involvement (control group) are shown in Table 1. At MCL diagnosis, non-CNS extranodal involvement was seen in 30 (83%) pts in the CNS MCL group (24 pts with 1 site and 6 pts with ≥ 2 sites), with bone marrow being the most common extranodal site of involvement (n=24, 67%). For the control group, 54 (75%) pts had extranodal involvement (44 pts with 1 site and 10 pts with ≥ 2 sites), and bone marrow was also the most common extranodal site of involvement (n=50, 69%). Notably, advanced stage disease (stage 3-4) was more commonly seen in the CNS MCL group (n=32, 97%) than in the control group (n=59, 83%) (p=0.04) at MCL diagnosis. Blastoid variant was present in a higher proportion of pts in the CNS MCL group (n=11, 31%) compared to the control group (n=8, 11%) (p=0.02). The CNS MCL group also presented with a higher median serum LDH at diagnosis (239 U/L [range 153-1901] vs. 187 U/L [range 124-588], p=0.02), and higher Ki-67 (40% [range 15-100] vs. 30% [range 10-90], p=0.04) compared to the control group. The most common frontline treatment regimen was anthracycline-based therapies (i.e. R-CHOP, Nordic regimen, R-hyperCVAD) for both groups (58% in CNS MCL group and 56% in control group). 14 (39%) pts in the CNS MCL group underwent autologous stem cell transplant in CR1 vs. 31 pts (43%) in the control group. Similar use of rituximab maintenance was seen in both groups (31% in CNS MCL group and 25% in control group). Median total lines of therapy from initial MCL diagnosis was 3 (range 1-9) in CNS MCL group and 2 (range 1-9) in the control group. The median follow-up from MCL diagnosis was 134 months (95% CI:119-163) for the entire cohort. Median OS from MCL diagnosis was 50.3 months (95% CI: 20.9-71.1) for the CNS MCL group compared to 97.1 months (95% CI: 82.6-192.7; p=<0.001) for the control group (Figure 1). Median time from MCL diagnosis to CNS involvement was 25 months (range 0-167). Median OS from CNS involvement was 4.7 months (95% CI: 2.3-6.7). At last follow up, 31 (86%) pts were deceased from the CNS MCL group, compared to 38 (52%) pts in the control group. For the CNS MCL group, the causes of death were CNS lymphoma in 10 (32%) pts, systemic lymphoma in 9 (29%) pts, treatment-related complication in 7 (23%) pts, and other/unknown in 5 (16%) pts. For the control group, the causes of death were systemic lymphoma in 15 (39%) pts, treatment-related in 2 (5%) pts, and other/unknown in 21 (55%) pts. Conclusion: In pts with MCL, CNS involvement is associated with worse outcomes as evident by a shorter median OS from initial MCL diagnosis (50 months vs. 97 months). Involvement of the CNS by lymphoma is an important contributor for the shorter OS as suggested by the median OS of only 5 months from CNS involvement. Advanced stage, blastoid variant, elevated LDH, and elevated Ki67 at MCL diagnosis were features more commonly seen in the CNS MCL cohort. Validation of risk factors at initial MCL diagnosis associated with CNS involvement and exploring the role of CNS prophylaxis are important topics for further investigation. Figure 1 Figure 1. Disclosures Paludo: Karyopharm: Research Funding. Wang: Novartis: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Research Funding; InnoCare: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding. Bennani: Purdue Pharma: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Vividion: Other: Advisory Board; Kymera: Other: Advisory Board; Verastem: Other: Advisory Board. Nowakowski: Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, NanoString Technologies, MorphoSys: Research Funding. Witzig: Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding. Habermann: Seagen: Other: Data Monitoring Committee; Tess Therapeutics: Other: Data Monitoring Committee; Incyte: Other: Scientific Advisory Board; Morphosys: Other: Scientific Advisory Board; Loxo Oncology: Other: Scientific Advisory Board; Eli Lilly & Co.,: Other: Scientific Advisor. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding.

Favorable Outcomes with Thiotepa/Busulfan-Based Conditioning and Autotransplant for Patients with Aggressive B-Cell Lymphoma and Secondary CNS Involvement

Introduction : Central nervous system (CNS) relapse is a devastating complication affecting ~5% of patients with diffuse large B-cell lymphoma (DLBCL). The optimal management is unknown and survival rates are ~20% in contemporary series. Thiotepa/busulfan-based high-dose chemotherapy (HDT) and autotransplant (ASCT) has demonstrated efficacy in primary CNS lymphoma, but there have been fewer studies of this conditioning regimen in secondary CNS lymphoma (SCNSL). Methods : This multicenter retrospective study included all consecutive patients ≥18 years old with aggressive B-cell lymphoma and secondary CNS involvement treated with thiotepa/busulfan-based HDT/ASCT at the University of Calgary and University of Alberta since 2005. Kaplan-Meier curves were used to estimate progression-free survival (PFS), overall survival (OS), and disease-specific survival (DSS) from the time of ASCT. Data collection is underway for all consecutively diagnosed SCNSL patients at our institutions to evaluate frequency and predictors of HDT/ASCT use. Results : This study included 57 patients with DLBCL (n=45), double-hit lymphoma (n=6), high-grade B-cell lymphoma NOS (n=2), intravascular large B-cell lymphoma (n=2), or T-cell/histiocyte-rich large B-cell lymphoma (n=2). Two (4%) had previously treated indolent B-cell lymphoma and 1 (2%) had multiply relapsed DLBCL. Median International Prognostic Index was 4 (range 0-5) at DLBCL diagnosis and median time to CNS relapse was 4 months (range 0-139). Median age was 58 years (range 20-73) and median ECOG was 3 (range 0-4) at diagnosis of SCNSL. CNS involvement was present at initial diagnosis in 20 (35%) patients or developed during frontline treatment in 10 (18%) or after completion of treatment in 27 (47%). For those without SCNSL at diagnosis, isolated CNS relapse occurred in 31 (84%) patients while 6 (16%) had concurrent CNS and systemic relapse. Most patients (n=54, 94%) received high-dose methotrexate (HD-MTX)-based multiagent induction chemotherapy (median HD-MTX doses 4, range 1-5) followed by peripheral blood stem cell mobilization with rituximab, dexamethasone, cytarabine, and cisplatin (R-DHAP) in 41 (72%). HDT conditioning regimens were thiotepa, busulfan, melphalan, rituximab (TBMR, n=52, 91%) or thiotepa, busulfan, cyclophosphamide (TBC, n=5, 9%). Median time from SCNSL diagnosis to ASCT was 116 days (range 7-201). Median time to neutrophil engraftment was 10 days (range 7-15) and to platelet engraftment 16 days (range 9-93). Overall response rates (ORR) for systemic/CNS disease were 93%/89% pre-ASCT and 95%/100% post-ASCT. Combined ORR pre-ASCT was 88%, with complete response in 21% and partial response in 67%. Two (4%) patients who developed CNS relapse immediately prior to ASCT achieved long-term remission after TBMR conditioning without any other systemic chemotherapy. With a median follow-up time of 4.0 years (range 0.1-15.9), PFS was 75% (95% CI 61-85%), OS was 76% (95% CI 62-86%), and DSS was 79% (95% CI 64-88%) at 4 years after ASCT. Lymphoma recurred in 9 (16%) patients at median 88 days (range 54-346) after ASCT with CNS relapse (n=4), systemic relapse (n=3), or both (n=2). There were 2 (4%) deaths due to peri-transplant toxicity and 1 (2%) death at 1.5 years due to therapy-related acute myeloid leukemia; no other unexpected toxicities of HDT/ASCT were observed. Among the 45 (79%) patients achieving long-term disease-specific survival, none were treated with CNS radiation therapy and only 1 (2%) had persistent neurocognitive impairment. There were no significant differences in DSS with respect to timing of CNS relapse, concurrent presence of systemic disease, or TBMR versus TBC conditioning (78% vs 80%, p=0.87). Conclusion : In one of the largest studies of this conditioning regimen in SCNSL to date, we found that high-dose thiotepa/busulfan-based conditioning with ASCT is associated with favorable outcomes for patients with aggressive B-cell lymphoma and secondary CNS involvement, with 4-year OS ~75% in this study. Although SCNSL has been historically associated with a poor prognosis, an increasing proportion of patients may achieve long-term survival after intensive therapy with HD-MTX-based induction and thiotepa/busulfan-based HDT and ASCT. Figure 1 Figure 1. Disclosures Chua: Eisai: Honoraria; Pfizer: Honoraria; Merck: Honoraria; Gilead: Honoraria. Stewart: Novartis: Honoraria; AstraZeneca: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Roche: Honoraria; Sandoz: Honoraria; Teva: Honoraria.

Peripheral T-Cell Lymphoma Involvement of the Central Nervous System: Impact of Novel Therapeutics on Clinical Outcomes

Primary Central Nervous System (CNS) involvement of peripheral T-cell lymphoma (PTCL) is a rare phenomenon, with a reported incidence ranging from 2% to 16.7%. Similarly, secondary CNS lymphoma with PTCL phenotype is rare, with an approximately 2-6% incidence. Both clinical situations lead to dismal outcomes. Given the rarity of CNS involvement with PTCL, our understanding of this clinical manifestation is limited to retrospective studies, which have identified risk factors for CNS involvement such as extranodal involvement, stage III-IV disease, bone marrow involvement as well as ATLL subtype. Herein, we characterize CNS involvement of PTCL over a 26-year time period at a single institution, identify if there are any factors that have a positive impact on survival, and extrapolate risk factors for CNS involvement from this dataset. From the years 1996-2020, 222 patients were diagnosed with PTCL, of those, 25 patients developed CNS involvement. All patients had secondary CNS involvement. Baseline characteristics including first-line therapy are noted in Table 1. Four patients received intrathecal methotrexate for CNS prophylaxis, all of which were patients with an ATLL diagnosis. The median time from initial diagnosis to CNS involvement was 4.77 months (0-64 months). Upon CNS diagnosis, the median time to death was 1.13 months. With a median of 2 lines of treatment (range 1-5), 12 patients were exposed to novel therapeutic agents (HDAC inhibitors [HDACis], brentuximab vedotin, pralatrexate) and/or clinical trials investigating epigenetic combinations. Of these patients, 10 patients were exposed to novel therapeutics and/or epigenetic based clinical trials in the 2 nd line setting. There was a trend towards improved overall survival with exposure to novel therapeutics and/or treatment on epigenetic based clinical trials (p=0.1) (Figure 1). With the majority of patients surviving <6 months from CNS diagnosis, there were three excellent responders that survived >12 months, all of which were exposed to novel therapeutics. Two of the three excellent responders were diagnosed with CNS involvement upon initial diagnosis, while 1 patient relapsed in the fourth-line setting with CNS involvement. All three of the excellent responders were exposed to novel therapeutics, particularly pralatrexate as a commonality in the second line setting. Using logistic regression, an ATLL diagnosis, extranodal involvement, and a high ECOG score were associated with a higher risk of CNS involvement. Unlike other studies, a high IPI score was not associated with a predilection for CNS involvement. In conclusion, we describe one of the largest single-center collection of CNS PTCL involvement. CNS involvement of PTCL is rare, with a reported cumulative incidence in this cohort of 11.3% over a 26-year time period. Risk factors that were identified include an ATLL diagnosis, extranodal involvement, and poor performance status. Exposure to novel therapeutics leads to a trend towards improved outcomes possibly secondary to improved disease control, but overall, the majority of patients had dismal outcomes. Notably, of the novel therapeutics interrogated, romidepsin and pralatrexate have low penetrance into the CNS, while there is no current evidence to suggest brentuximab vedotin is able to cross the blood-brain barrier. The possibility of a disturbed blood-brain barrier to permit improved penetrance of these drugs is plausible, but further studies are warranted to support this. Although a small percentage of patients will suffer from CNS PTCL, there is a dire need to improve therapy for this patient population and to establish universal metrics to identify patients that are at risk of CNS involvement. Moreover, given the rarity of CNS PTCL involvement, a future endeavor would be to validate these findings in larger, multicenter initiative. Figure 1 Figure 1. Disclosures Lue: AstraZeneca: Speakers Bureau; Kymera Therapeutics: Research Funding; TG Therapeutics: Consultancy; Epizyme: Consultancy; Kura Oncology: Consultancy. Marchi: Astex: Research Funding; Kyowa Kirin: Honoraria; Merck: Research Funding; BMS: Research Funding; Myeloid Therapeutics: Honoraria; Kymera Therapeutics: Other: Scientific Advisor. O'Connor: Myeloid Therapeutics: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Servier: Research Funding; Kymera: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; BMS: Research Funding; Merck: Research Funding; TG Therapeutics: Current Employment, Current equity holder in publicly-traded company.

Promising Real World Survival Data in Adult-Onset Langerhans Cell Histiocytosis: An Australasian Lymphoma Alliance 20 Year Retrospective Study

Background: Langerhans Cell Histiocytosis (LCH) is a rare inflammatory neoplasm originating from bone marrow-derived CD207+/CD1+ clonal dendritic cells, with cells expressing BRAF V600E in around 50% of cases. Although more common in the paediatric setting, LCH is rare in adults, with an incidence of 1 to 2 cases per million. This combination of disease heterogeneity and infrequency means that data on treatment strategies and outcomes is limited, and a consensus on management is lacking. Data has historically been extrapolated from the larger paediatric cohort, with emerging phase II data on the efficacy and safety of upfront methotrexate and cytosine arabinoside (AraC) in adult LCH. Other agents used include cladribine (CdA), hydroxyurea, vinblastine, and prednisolone-based regimens, and more recently MEK/BRAF inhibitors, but none of these have been trialled prospectively. LCH can be an aggressive disease with a poor prognosis. Methods : We included patients aged ≥18 years diagnosed with LCH on histopathology between January 1, 2000 and August 1, 2021 from ten sites across Australia and New Zealand. Variables included demographic data, system and organ involvement, central nervous system (CNS) involvement, bone marrow involvement and BRAF V600E mutation status. Outcomes measured included overall survival (OS), progression-free survival (PFS) and total lines of therapy. Response to therapy was modified from the Scoring System of the HS LCH III trial: Complete response (CR) was defined by resolution of all signs of disease activity, including neuroendocrine dysfunction, skin and radiological lesions; and a partial response (PR) was defined as patients with "active disease better" and those with "mixed response". Stable or worsening symptoms/radiology were classified as progressive disease (PD). Patients who were alive or lost to follow-up were censored on the date of last follow-up. Results : We identified 46 patients with a median age at diagnosis of 39 years (range 18-81) (Table 1). The sex ratio was 1. 41% of patients had MS-LCH at diagnosis, of which 24% had high risk organ (liver, bone marrow, or spleen) involvement. 37% had multifocal bone disease. 28% of patients had CNS involvement at diagnosis. BRAF V600E mutation status was assessed in only 43% of cases, with a mutation frequency of 40%. The median number of lines of therapy was 1.7 (range 0-9). Three patients (7%) underwent lung transplantation for isolated pulmonary LCH. 31% percent of patients were treated with chemotherapy upfront, with the majority receiving AraC (43%,) and the remainder receiving vinblastine, prednisolone and 6-mercaptopurine (6-MP) (21%), vinblastine/prednisolone (21%), CdA (14%) or methotrexate and 6-MP (2%). Of note, 67% (n=4) of patients who were treated with upfront AraC and 100% (n=2) of patients treated with upfront CdA had a CR, while those patients treated with upfront vincristine-based regimes had, at best, a PR (50%, n=3) or PD (50%). Of the 46 patients, with a median follow up of 34.6 months (range 0.63-250.2), there were 7 deaths (15%) with 6/7 due to progressive disease, and the remaining death due to complications of lung transplantation. Median OS was not reached (Figure 1), while OS at 5 years was 85%. Median PFS was 9 years (range 0.05-21) (Figure 2), with a non-significant trend towards reduced PFS in patients with MS-LCH (5 years) compared to SS-LCH (9 years) (Figure 3). There was also a trend towards reduced OS in patients who received AraC as systemic therapy versus other forms of systemic therapy. Conclusion: We report the largest multicentre Australasian cohort of patients diagnosed with adult-onset LCH. OS and PFS were longer than previously reported in the literature. There remains significant heterogeneity in diagnostic and treatment strategies. There was a trend towards improved response rate to upfront AraC or CdA when compared to the vinblastine-based regimens, and further prospective research with these agents is required in this setting. Progress in this disease is challenging due its rarity, highlighting the need for standardisation of diagnostic and treatment strategies as well as a national and/or international registry. Figure 1 Figure 1. Disclosures Fong: Amgen: Research Funding; AbbVie, Amgen, Novartis, Pfizer, Astellas: Honoraria; Amgen, BMS: Speakers Bureau. Ku: Antegene: Consultancy; Roche: Consultancy; Genor Biopharma: Consultancy. Cunningham: Principia Biopharma: Research Funding; Rigel: Research Funding; Janssen: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Amgen: Research Funding; Astex: Research Funding; Celgene: Research Funding. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Primary Central Nervous System Involvement at Initial Diagnosis Remains an Independent Risk Factor for Relapse in Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Cell Transplantation in CR1

Background: A recent study from the Acute Leukemia Working Party of EBMT demonstrated that outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) for adults with acute lymphoblastic leukemia (ALL) have improved significantly over time and that total body irradiation (TBI) should be considered as the preferable type of myeloablative conditioning (MAC). This study, however, did not compare outcomes of allo-HCT in patients with CNS involvement (CNS-pos) vs. those without CNS disease (CNS-neg). Study population: Here, we evaluate post allo-HCT outcomes of 547 patients (CNS-pos at initial presentation=96, CNS-neg=451) who underwent the procedure in first complete remission (CR1) between 2009 and 2019 at an EBMT participating transplant center. The distribution of ALL subtypes were as follows: CNS-pos (Ph-neg B ALL=28%, Ph-pos B ALL=27%, and T-cell ALL=45%) and for CNS-neg (Ph-neg B ALL=21%, Ph-pos B ALL=44%, and T-cell ALL=35%), p=0.01. The primary endpoint was leukemia-free survival (LFS). Results: The median follow up was not statistically different between the CNS-pos (78.7 months) and the CNS-neg group (67.2 months), p=0.58. Patients in the CNS-pos group were younger (median age 31.3 vs. 39.7 years, p=0.004), received the procedure more recently (median year 2012 vs. 2010, p=0.003), were less likely to have a Karnofsky score of equal or higher than 90 (70.8% vs. 81.9%, p=0.017), or to have received peripheral blood stem cells (PBSC) (61.5% vs. 72.7%, p=0.028). The groups did not differ in regards to donor source (URD, 50% vs. 56.5%, p=0.24) or the intensity of the preparative regimen (MAC, 82.3% vs. 85.6%, p=0.41). In multivariate analysis, CNS-pos were associated with higher cumulative incidence of relapse (HR=1.58 (95%CI=1.06-2.35), P=0.025) and a trend for an inferior leukemia-free survival (LFS) (HR=1.38 (95%CI=0.99-1.92), p=0.057), but did not adversely impact overall survival (OS) (HR=1.28 (95%CI=0.89-1.85), p=0.18). A subgroup multivariate analysis limited to patients with CNS-pos showed that prescribing a TBI MAC regimen (vs. others) results in a lower cumulative incidence of relapse (HR=0.35 (95%CI=0.15-0.79), p=0.012) and better LFS (HR=0.43 (95%CI=0.22-0.83), p=0.01) and OS (HR=0.44 (95%CI=0.21-0.92), p=0.03). Use of PBSC (vs. BM) was also independently associated with better OS (HR=0.53 (95%CI=0.29-0.99), p=0.046). Conclusion: Notwithstanding the inherent limitations of registry data, particularly ascertaining the absence of CNS involvement in the CNS-neg group, our results show CNS involvement as an independent risk factor for relapse following allo-HCT. Our data support, nonetheless, the choice of a TBI-based MAC regimen in this group of patients but stresses the need for close monitoring of relapse after allo-HCT. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Bazarbachi: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hikma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Mielke: Immunicum: Other: Data safety monitoring board; DNA Prime SA: Speakers Bureau; Gilead/KITE: Other: Travel support, Expert panel ; Miltenyi: Other: Data safety monitoring board; Novartis: Speakers Bureau; Celgene/BMS: Speakers Bureau. Socie: Alexion: Research Funding. Huynh: Jazz Pharmaceuticals: Honoraria. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Giebel: Janssen: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Peric: Therakos, Servier, MSD, Astellas, Novartis, Abbvie, Pfizer: Honoraria. Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria.

Clinicopathologic Characteristics and Genomic Profiling of De Novo CD5 Positive Diffuse Large B-Cell Lymphoma: A Multicenter Retrospective Study in China

De novo CD5 positive diffuse large B cell lymphoma (CD5+ DLBCL) has poor survival in the era of immunochemotherapy. We conducted a multi-center retrospective study to explore the clinicopathologic characteristics, genomic profiling and prognostic elements of 61 CD5+ DLBCL and 60 CD5- DLBCL patients in China. In contrast with CD5- DLBCL, elderly onset, advanced stage, central nervous system (CNS) involvement, as well as MYC/BCL-2 and P53 overexpression were more prevalent in CD5+ DLBCL. In addition, most of CD5+ DLBCL patients were of non-germinal center B-cell-like (non-GCB) and activated B-cell-like (ABC) subtype according to immunohistochemistry and Lymph2Cx assay. Genetic analysis by next generation sequencing (NGS) showed the proportion of MCD subtype in CD5+ DLBCL was higher than that of CD5- DLBCL (50% vs 5%, p = 0.0007). Compared with CD5- cohort, CD5+ DLBCL patients showed poorer 5-year overall survival (OS) (70.9% vs 39.0%, p<0.001), independent of cell-of-origin and MYC/BCL-2, P53 and BCL-6 status. Multivariate analysis showed that age >76 years, advanced stage, CNS involvement and hypoalbuminemia were independent factors associated with poor prognosis in CD5+ DLBCL. In conclusion, CD5+ DLBCL conveyed poor prognosis and showed distinctive clinicopathologic characteristics and predominant genetic features of ABC and MCD subtypes. Disclosures No relevant conflicts of interest to declare.