Prophylactic Intrathecal Chemotherapy Research Articles

Incidence and Risk Factors for Central Nervous System Relapse after Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Acute Lymphoblastic Leukemia

Background Acute lymphoblastic leukemia (ALL) is frequently accompanied with the involvement of the central nervous system (CNS). The clinical prognosis for ALL patients with CNS disease is generally unfavorable, and prophylactic measures such as intrathecal chemotherapy are highly recommended. In adult ALL patients, hematopoietic stem cell transplantation (HSCT) presents a potential curative approach. However, there are currently only a few reports available on the risk factors and epidemiology of CNS relapse after HSCT. Method We conducted a retrospective single-center cohort study involving 1043 patients diagnosed with either acute lymphoblastic leukemia (ALL) or mixed phenotype acute leukemia (MPAL). These patients were treated at our center using the same treatment protocol between 2009 and 2022. During the remission induction phase, we utilized a modified hyper-CVAD regimen, along with six rounds of prophylactic intrathecal (IT) chemotherapy. High-risk patients who had suitable donors underwent allogeneic hematopoietic stem cell transplantation (HSCT) as part of their post-remission therapy. Diagnosis of central nervous system (CNS) leukemia was established when neurologic symptoms were observed in correlation with CNS lesions on imaging studies, or when leukemic blasts were detected in the cerebrospinal fluid (CSF). In our study, we examined the incidence, risk factors, and survival outcomes of patients who experienced CNS relapse after transplantation. Results Among the entire cohort of 1043 patients, CNS involvement was observed in 3 (0.3%) patients at initial diagnosis and 12 (1.2%) during chemotherapy. We proceeded with allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 755 consecutive patients. Among these 755 patients, 3 had CNS leukemia prior to transplantation. Among the group of 755 patients, a total of 224 (29.6%) experienced relapse. Of these relapses, 142 (18.8%) were bone marrow relapses alone, 54 (7.1%) were extramedullary relapses alone (with CNS involvement in 21 [38.8%]), and 28 (3.7%) had both bone marrow and extramedullary relapses (with CNS involvement in 13 [46.4%]). Overall, extramedullary relapse was observed in 82 (10.8%) patients, with CNS involvement in 34 (4.5%) cases, following allo-HSCT. The 5-year cumulative incidence of CNS relapse was 4.6%, which was significantly higher in patients with Philadelphia chromosome-positive (Ph-positive) ALL (9.4% vs. 1.0%, p <0.001), as well as those with a high leukocyte count at diagnosis (8.3% vs. 2.6%, p = 0.001). Among the Ph-positive ALL cases, a high leukocyte count (n=151) was associated with a higher prevalence of pre-HSCT minimal residual disease (MRD) > 0.1% (n=88), which exhibited a significantly increased incidence of CNS relapse (16.6% vs. 6.8%, p = 0.009). Factors such as age, number of intrathecal chemotherapy treatments, conditioning intensity, and dose of anti-thymocyte globulin did not have a significant impact. Among the 34 patients with CNS relapse, 21 (61.7%) had isolated CNS relapse, and 7 of them showed evidence of positive MRD. With the exception of one patient who refused further treatment, the remaining 33 patients received initial CNS local therapy, including intrathecal chemotherapy combined with radiotherapy in 27 (82.0%) cases, intrathecal chemotherapy alone in 6 cases, and radiotherapy alone in 4 cases. Out of these patients, 22 were treated with dasatinib or ponatinib, while 6 received salvage chemotherapy. The median overall survival for patients with CNS relapse was 11.2 months, which was 19.8 months for those with isolated CNS relapse and 10.9 months for those with CNS relapse accompanied by bone marrow relapse (p = 0.077). The subsequent 2-year cumulative incidence of CNS relapse was 30%. Conclusion Based on our findings, the current prophylaxis strategy employed for the prevention of post-HSCT CNS relapse in adult ALL appears to be effective. However, our data indicates that MRD-positive Ph-positive ALL requires distinct management due to its significantly elevated risk of CNS relapse. New strategies including prophylactic radiotherapy for this high-risk subgroup must be considered to prevent post-HSCT CNS disease.

Clinical Course of Adult T-Cell Leukemia-Lymphoma with Central Nervous System Involvement

Background: Adult T-cell leukemia-lymphoma (ATL) is a peripheral T-cell lymphoma with a highly diverse clinical presentation. Although central nervous system (CNS) involvement is common, the detailed clinical presentation of CNS-ATL needs to be clarified. Objective: This study aims to clarify the clinical course of ATL with CNS involvement. CNS involvement was classified according to the criteria of JALSG202 for acute lymphocytic leukemia as follows: Grade I: no symptoms and cerebrospinal fluid (CSF)cell count less than 5/μl and presence of abnormal lymphocytes; Grade II: asymptomatic and CSF cell count 5-50/μl and presence of abnormal lymphocytes; Grade III: symptomatic or CSF cell counts > 50 cells/μl and presence of abnormal lymphocytes. Results: The analysis included 213 cases of ATL treated at Kagoshima University Hospital from 2002 to 2021. Of these aggressive ATL cases, the clinical subtypes at initial presentation were as follows: acute type 109, lymphoma type 54, chronic type 30, smoldering type 18, and 2 cases were unclassifiable. The median age of the patients was 63 years, and 96 cases (45.1%) were women. Sixty patients had received allogeneic hematopoietic stem cell transplants. During the clinical course, 28 patients (13.1%) with a median age of 61 years and 13 women（46.4%）had CNS involvement. Two cases were classified as Grade I, six as Grade II, and 20 as Grade III. Among them, nine patients (4.2%) showed neurological symptoms at the initial ATL diagnosis, and 1 patient presented with neurological findings at the time of chronic to acute transformation. Of the remaining 203 patients, prophylactic intrathecal chemotherapy was administered in 101 cases, at which time CNS involvement was diagnosed in 9 cases (8.9%). Three patients developed symptomatic involvement while responding to chemotherapy. One patient developed symptomatic involvement when refractory to chemotherapy. Four cases were CNS recurrence with systemic disease progression after remission. Two cases were identified as primary CNS-ATL. The simplified ATL-PI (Prognostic Index) at initial ATL diagnosis for the 28 patients with CNS involvement revealed four cases with high-risk, thirteen with intermediate-risk, two with low-risk, six not eligible due to indolent ATL subtypes, and three cases with unknown risk. The incidence of CNS involvement by ATL subtype was 17.8% (19/107) for acute type, 1.8% (1/54) for lymphoma type, 16.7% (5/30) for chronic type, and 0% for smoldering type (excluding 1 case of unknown subtype and 2 cases of primary CNS-ATL) at ATL diagnosis. At the diagnosis of CNS involvement, 15 (53.6％) patients showed at least 5% of ATL cells in the peripheral blood. During a median observation period of 429 days, the 1-year cumulative incidence of CNS involvement was 12.3% (95% CI 8.3-17.1%). High-dose methotrexate-based therapy was administered to 5 patients with CNS involvement, which had a certain effect on CNS lesions but had limited efficacy for other lesions. All of these cases were treated with concomitant intrathecal chemotherapy. The 2-year overall survival rate after diagnosis of CNS involvement was 16.9% (95% CI 4.9-35.2%). The CNS-IPI (International Prognostic Index) did not predict CNS involvement in ATL. Conclusions: This is the largest study to examine the clinical course of CNS involvement of ATL. The 1-year cumulative incidence of CNS involvement was 12.3%, indicating that CNS involvement is an early complication after diagnosis of aggressive ATL, especially in leukemic subtypes. The prognosis after the diagnosis of CNS involvement was also clarified. The high frequency of CNS involvement during prophylactic intrathecal chemotherapy in patients with ATL without neurological symptoms suggests that it is an important clinical question that needs to be addressed.

Chemotherapy-Free Combination of Blinatumomab and Ponatinib in Adults with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Updates from a Phase II Trial

Background Blinatumomab and ponatinib demonstrated efficacy in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). A chemotherapy-free regimen combining both drugs in the frontline setting may mitigate the risk of toxicities and the need for hematopoietic stem cell transplantation (HSCT). Methods In this phase II trial, patients ≥18 years of age with newly diagnosed Ph-positive ALL were eligible. They were required to have a performance status of ≤2, total bilirubin ≤2x the upper limit of normal (ULN), and ALT/AST ≤3x the ULN. Patients with uncontrolled cardiovascular disease or clinically significant central nervous system (CNS) comorbidities (except for CNS leukemia) were excluded. Patients received up to 5 cycles of blinatumomab in combination with ponatinib, followed by ponatinib maintenance for ≥5 years. Ponatinib 30mg daily was given during Cycle 1 and decreased to 15mg daily once a complete molecular response (CMR) was achieved. Patients also received 12 doses of prophylactic intrathecal (IT) chemotherapy with alternating cytarabine and methotrexate. The primary endpoint was the CMR rate. Secondary endpoints included response rates, safety measures, event-free survival (EFS), and overall survival (OS). Results Between June 2018 and May 2023, 62 pts with newly diagnosed Ph-positive ALL were treated. Baseline characteristics are shown in Table 1. Twenty-two patients were in complete remission (CR) at the start of therapy. Among 40 patients evaluable for hematologic response, 39 (98%) achieved CR/CRi; 1 patient had early death. Among 55 patients evaluable for molecular response, 37 (67%) achieved CMR after 1 cycle, and 46 (84%) achieved CMR at any time. Forty-seven patients were evaluated for measurable residual disease (MRD) by next-generation sequencing at a sensitivity level of 10 -6, of whom 43 (91%) were found to have negative MRD. Five of these patients with undetectable MRD by NGS had low-level BCR:ABL1 transcripts detected by PCR at the same time (ranging from 0.01% to 1.23% IS). Four of them had p190 transcript and one had p210. The median follow-up was 17 months (range, 2-61 months). Six patients (10%) relapsed after a median of 21 months of remission (range, 8-24 months): two relapsed in the bone marrow (one with acquired E225V mutation), one had an extramedullary-only relapse (Ph-negative and MYC-rearranged relapse), and three had a CNS-only relapse (after 20, 22, and 23 months). Four patients died (one from intracranial hemorrhage, one from post-procedural hemorrhage, one from brain aneurysm, and one following CNS relapse with intracranial edema and septic shock). One leukemia-related death occurred on study; the estimated 2-year EFS and OS rates were 77% and 89%, respectively (Figure 1). Only one patient underwent HSCT in first CR due to persistently low-level BCR:ABL1 positivity. Among the 52 patients in ongoing remission without HSCT, the median duration of response was 16 months (range, 2-61). Most adverse events were grade 1-2 and were consistent with the known toxicity profile of the two agents. Ponatinib was discontinued in two patients due to possibly related adverse events (cerebrovascular accident and coronary artery stenosis in one patient each). Conclusions The chemotherapy-free combination of blinatumomab and ponatinib is safe and effective in newly diagnosed Ph-positive ALL, with high rates of MRD negativity. Encouraging duration of remission and OS has been observed without the need for HSCT.

Evaluating the Impact of Prophylactic Intrathecal Chemotherapy in Diffuse Large B Cell Lymphoma (DLBCL) Patients with High Central Nervous System International Prognostic Index (CNS-IPI) Scores: A Comprehensive Review and Meta-Analysis

Introduction Diffuse large B cell lymphoma (DLBCL) with a high CNS-IPI score poses an increased risk for relapse involving the central nervous system (CNS). Despite various studies seeking to validate the use of CNS prophylaxis, including intrathecal chemotherapy, results have been equivocal. This ambiguity may be partly attributed to the lack of prospective data, patient heterogeneity, limited sample sizes, and outdated methodologies in pre-rituximab studies. Consequently, administering CNS prophylaxis with intrathecal chemotherapy is not a standardized practice, and decisions are often based on individual factors such as anatomical location, disease stage, and specific case characteristics. Methods This systematic review and meta-analysis were conducted and reported using the PRISMA guidelines. A thorough search was conducted across multiple online databases, including Google Scholar, Science Direct, PubMed, Cochrane, CINAHL, EMBASE, ProQuest Dissertation and Theses, ISI web of knowledge, PsycINFO, and Embase for articles on this topic. The date range of the articles included was between 2013-2023 and were limited to English language, peer-reviewed articles, cohort studies, retrospective studies & randomized controlled trials. The inclusion and exclusion criteria for studies helped to determine suitable studies Results Out of 179 studies retrieved from the database search and 2 from other studies' reference lists, 6 met the inclusion criteria for qualitative and quantitative analysis. Data from 2209 patients in these 6 studies was analyzed using a random-effects model to perform a subgroup analysis of the benefits and risks of prophylactic intrathecal chemotherapy for patients with DLBCL and a high CNS-IPI score. The results demonstrated a significant improvement in overall treatment success, with a difference of 0.60 (95% Confidence Interval, 0.45 to 0.93) on a 0-10 Visual Analogue Scale (VAS). The heterogeneity of the studies was determined to be significant (P=0.02), further substantiating the positive impact of prophylactic intrathecal chemotherapy on the therapy success rate for DLBCL patients with high CNS-IPI scores. Conclusion Our review elucidates that intrathecal chemotherapy as a prophylactic measure can reduce the rate of CNS relapse and enhance overall survival for patients with DLBCL possessing a high CNS-IPI score. However, it underscores the necessity to thoroughly assess each patient's unique clinical situation when determining if intrathecal chemotherapy is the appropriate therapeutic approach.

Subgroup analysis from a phase II trial of ponatinib and blinatumomab in relapsed/refractory (R/R) Philadelphia chromosome-positive acute lymphoblastic leukemia or chronic myeloid leukemia in lymphoid blast phase.

e19038 Background: The chemotherapy-free combination of ponatinib and blinatumomab improved outcomes in patients (pts) with newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). This regimen may also induce deeper responses and prolong remissions in patients (pts) with R/R Ph+ ALL and chronic myeloid leukemia in lymphoid blast phase (CML-LBP). Methods: In this phase II trial, pts with R/R Ph+ ALL or CML-LBP received up to 5 cycles of blinatumomab. Pts received ponatinib 30mg daily in Cycle 1, with dose reduction to 15mg daily once in complete molecular response (CMR). After completion of blinatumomab, ponatinib was continued for at least 5 years. 12 doses of prophylactic intrathecal chemotherapy were administered in all pts. Results: 21 pts were treated (14 R/R, 7 CML-LBP) between 2/2018 and 7/2022. The median age of the R/R Ph+ ALL and CML-LBP cohorts were 38 years (range, 24-61) and 67 years (range, 29-82), respectively. BCR:ABL1 transcripts were p190 in 93% of the R/R cohort. 43% of pts in the R/R Ph+ ALL cohort were in Salvage 2+. Among the CML-LBP pts, 4 were de novo and 3 were transformed from previously treated CML (1 of whom had received prior therapy for LBP). Among the 14 pts with R/R Ph+ ALL, the rate of CR/CRi was 92% (12 of 13 evaluable pts), with CR in 11 (85%) pts. MMR was achieved in 86% and CMR in 79%. Six of 7 (86%) pts with CML-LBP achieved CR/CRi. Rates of MMR and CMR were 57% and 43%, respectively. The median follow-up is 24 months (range, 19-57) in the R/R cohort, and 27 months (range, 7-46) in the CML-LBP cohort. Among the 14 pts in the R/R cohort, 1 did not respond, 6 proceeded to ASCT (1 of whom relapsed and died), 4 did not undergo ASCT and relapsed after a median of 6.4 months (range, 2.7-8.1), 1 died in CR, and 2 are in ongoing response without ASCT after a median CR duration of 34 months (range, 17-51). Of the 5 relapses, 2 were hematologic only, 2 were in the CNS with MRD positivity in the bone marrow, and 1 was CNS only. The estimated 2-year EFS and OS for the R/R cohort were 50% and 64%, respectively. Among the 6 responders in the CML-LBP cohort, 3 relapsed and 3 are in ongoing response without ASCT after a median CR duration of 34 months (range, 3-43). The 2-year EFS and OS for the CML-LBP cohort are 38% and 50%, respectively. Grade 3 adverse events were febrile neutropenia, cytokine release syndrome, elevation of lipase and alkaline phosphatase in 1 pt each. There were no Grade 4-5 events. 1 pt discontinued ponatinib due to grade 3 portal vein thrombosis. 1 pt discontinued blinatumomab due to persistent grade 2 tremor. Conclusions: The combination of ponatinib and blinatumomab is an effective and well-tolerated chemotherapy-free regimen for pts with R/R Ph+ ALL. The rate of deep molecular response was relatively low in CML-LBP, suggesting that chemotherapy might still be needed in these pts. Clinical trial information: NCT03263572 .

Olverembatinib Plus Low-Intensive Regimen in Frontline Therapy for Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia： a Case Series from a Single Center

BCR::ABL1 tyrosine kinase inhibitors (TKI) have shown promising results in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). However, resistance and intolerance to TKIs remains a clinical challenge. Olverembatinib is an oral, novel third-generation TKI developed by Ascentage Pharma. Olverembatinib is effective against most ABL1 kinase domain mutants, including mutant T315I. In November 2021, olverembatinib was approved in China for the treatment of adults with BCR::ABL1T315I-mutant chronic myeloid leukemia (CML). However, data on clinical use of olverembatinib in Ph+ ALL are very limited. Herein, we report a retrospective analysis of patients with newly diagnosed Ph+ ALL who received olverembatinib plus low-intensive regimen (VP: Vindesine + dexamethasone / prednisone ) at our institution. Olverembatinib was administered at a dose of 40 mg orally QOD continuously. Vindesine was given 4 mg intravenously on day 1, 8, 15, 22 and dexamethasone /prednisone was administered from days 1 to 22 during induction. After two courses of olverembatinib plus VP, olverembatinib-based regimens was recommended for consolidation. The choice of sequentially consolidation treatment with allogeneic hematopoietic stem-cell transplantation (allo-HSCT), blinatumomab or intensive chemotherapy, was made by the investigators and patients preference. Prophylactic intrathecal chemotherapy with cytarabine and dexamethasone was administered in each cycle. Maintenance therapy was olverembatinib and low-intensive regimens. The primary endpoint was complete molecular response (CMR) rate. CMR was defined as BCR-ABL1/ABL1 ratio < 0.01% by quantitative real-time polymerase chain reaction(qPCR). Between November 2021 and June 2022, a total of 12 consecutive patients with Ph +ALL treated with the olverembatinib plus VP at our center were enrolled. The median age was 48 years (range, 18-72 years). Ten patients were male and two were female. The median white-cell counts were 77,000 per cubic millimeter (range, 1200 to 356,000). Seven patients had the p190 fusion transcript, five had the p210 transcript. All 12 patients completed induction phase with olverembatinib plus VP regimen. At the end of the 4 weeks of induction , all 12 patients (100%) achieved complete hematologic response. The primary endpoint CMR was reached in 6/12 patients (60%) at 4 weeks; in 12/12 patients (100%) at 8 weeks. For treatment-emergent adverse events, most of which were mild and manageable. No serious nonhematologic toxicities were observed. With a median follow-up of 5 months, all patients were in CMR in the last follow-up, four patients proceeded to allo-HSCT. Conclusions: Olverembatinib was well tolerated and showed high early response in newly diagnosed Ph +ALL. These promising findings warrant further investigation in future trials.

A Phase II Study of the Sequential Combination of Low-Intensity Chemotherapy (mini-hyper-CVD) and Ponatinib Followed By Blinatumomab and Ponatinib in Patients with Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL)

Background Hyper-CVAD plus ponatinib is highly effective in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). The sequential combination of low-intensity chemotherapy and ponatinib followed by blinatumomab and ponatinib may lead to deeper and more durable responses, while minimizing toxicity of intensive chemotherapy and sparing the need for allogenic stem cell transplantation (ASCT). Methods In this phase II study, adults with either newly diagnosed (ND) Ph+ ALL, relapsed/refractory (R/R) Ph+ ALL, or chronic myeloid leukemia in lymphoid blast phase (CML-LBP) were eligible. Patients (pts) in the ND cohort could have received up to two cycles of therapy prior to enrollment. Pts received mini-hyper-CVD alternating with methotrexate and cytarabine on cycles 1-4, followed by blinatumomab and ponatinib on cycles 5-8. Ponatinib 30mg daily was given in cycle 1, and the dose was reduced to 15mg daily once a complete molecular response (CMR) was achieved. Pts with CD20+ disease received rituximab on cycles 1-4. Pts received 12 total administrations of prophylactic intrathecal chemotherapy with alternating cytarabine and methotrexate. Following consolidation, pts received maintenance therapy with 15 cycles of ponatinib plus vincristine/prednisone (maintenance cycles 1-3, 5-7, 9-11, and 13-15) alternating with ponatinib plus blinatumomab (maintenance cycles 4, 8, and 12) followed by ponatinib monotherapy daily for at least 5 years. The primary endpoint for pts with ND Ph+ ALL was the CMR rate. The primary endpoint for pts with R/R Ph+ ALL or CML-LBP was the CR/CRi rate. Secondary endpoints included complete remission duration (CRD), overall survival (OS), and safety. Results Between November 2019 and December 2021, 16 pts were treated (11 ND, 3 R/R, 2 CML-LBP). Baseline characteristics are shown in Table 1. The median age of the ND cohort was 35 (range, 25-59). BCR::ABL1 transcripts were p190 in 7 (64%) pts in the ND cohort. All pts in the R/R and CML-LBP cohorts were p210. Five pts (31%) in the ND cohort had evidence of a myeloid component to their disease (BCR::ABL1 in the myeloid compartment by FISH analysis in 4 pts and a small population of myeloid blasts in 1 pt). One of the R/R pts was in salvage 1, and 2 pts were in salvage 2; none of the R/R pts had previously received ponatinib. Neither of the 2 pts with CML-LBP had received any prior therapy, including a TKI. Nine pts (6 ND, 2 R/R and 1 CML-LBP) were in CR at the time of enrollment, and 4 pts (3 ND and 1 R/R) were in CMR. All pts who were evaluable for morphological response achieved CR. Among 8 evaluable ND pts, 6 achieved CMR. Two of 3 evaluable R/R pts and 1 of 2 evaluable CML-LBP pts achieved CMR. Among the 9 pts who achieved CMR, all but one achieved CMR during the chemotherapy plus ponatinib cycles. Out of the 5 ND pts who had evidence of myeloid involvement at presentation, 2 did not achieve CMR (both p190). All 6 pts who underwent Clonoseq MRD assessment achieved MRD negativity at 10-6 by this assay. With a median follow-up of 23 months (range, 6-31), the 2-year CRD and OS rates are 90% and 78%, respectively, across all cohorts (Figure 1), and are 89% and 82%, respectively in the ND cohort. Among the 11 ND pts, 1 pt (9%) relapsed, 2 pts (18%) died in CR (both due to COVID-19), and 8 pts (73%) are in continuous remission without ASCT. The 1 ND pt who relapsed developed CNS-only relapse during maintenance in the setting of non-compliance with ponatinib. Among the 3 R/R pts, no pts relapsed, 1 pt underwent ASCT, 1 pt died in CR from methotrexate-associated disseminated necrotizing leukoencephalopathy (autopsy-proven), and 1 pt is alive in continuous remission without ASCT. Among the 2 CML-LBP pts, neither relapsed, 1 pt underwent ASCT in first remission, and both are alive. Treatment was overall well-tolerated. The ponatinib dose was reduced in 2 pts prior to obtaining CMR due to toxicity (1 pancreatitis, 1 cardiomyopathy). One pt discontinued ponatinib and switched to dasatinib due to pulmonary embolism that occurred in cycle 2. No pts required dose-reduction or discontinuation of blinatumomab. The 30- and 60-day mortality rates were 0%. Conclusion Sequential combination of low-intensity chemotherapy and ponatinib followed by blinatumomab and ponatinib is highly effective and well tolerated in Ph+ ALL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Interactome based identification and validation of prefoldin 5-α for prognosing CNS leukemia in B-ALL patients

We report here the identification and validation of prefoldin 5-alpha (PFDN5-α) for the first time as prognostic biomarker for prediction of central nervous system (CNS) leukemia of B cell acute lymphoblastic leukemia (B-ALL) origin. Since cerebrospinal fluid (CSF) cytology being the gold standard of diagnosis for CNS leukemia with poor sensitivity, mandatory prophylactic intrathecal chemotherapy is administered irrespective of patients develop CNS leukemia. Thus, using interactome studies, we identified PFDN5-α as a prognostic biomarker for predicting CNS leukemia by interacting lymphoblastic proteins and CSF from B-ALL patients using far-western clinical proteomics approach. Validation by both western and ELISA methods confirmed our results. For further clinical translation, we performed Receiver Operating Characteristic (ROC) curve analysis generated from CNS +ve (n = 25) and −ve (n = 40) CSF samples from B-ALL patients and identified PFDN5-α-CSF reactivity cut-off value as 0.456. Values below 0.456 indicate the patient is at risk of developing CNS leukemia and suggestive of having intrathecal chemotherapy. Further flow cytometry validation for CNS leukemia positivity revealed that with increasing blast cells, a decrease in PFDN5-α-CSF reactivity confirming ELISA based PFDN5α-CSF reactivity assay. Predicting CNS leukemia development risk by ELISA based PFDN5-α-CSF reactivity assay could have potential in the clinical management of CNS leukemia.

Updated Results of a Phase II Study of Ponatinib and Blinatumomab for Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Updated Results of a Phase II Study of Ponatinib and Blinatumomab for Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

INCB84344-201: Ponatinib and steroids in frontline therapy for unfit patients with Ph+ acute lymphoblastic leukemia

AbstractTyrosine kinase inhibitors have improved survival for patients with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). However, prognosis for old or unfit patients remains poor. In the INCB84344-201 (formerly GIMEMA LAL 1811) prospective, multicenter, phase 2 trial, we tested the efficacy and safety of ponatinib plus prednisone in newly diagnosed patients with Ph+ ALL ≥60 years, or unfit for intensive chemotherapy and stem cell transplantation. Forty-four patients received oral ponatinib 45 mg/d for 48 weeks (core phase), with prednisone tapered to 60 mg/m2/d from days-14-29. Prophylactic intrathecal chemotherapy was administered monthly. Median age was 66.5 years (range, 26-85). The primary endpoint (complete hematologic response [CHR] at 24 weeks) was reached in 38/44 patients (86.4%); complete molecular response (CMR) in 18/44 patients (40.9%) at 24 weeks. 61.4% of patients completed the core phase. As of 24 April 2020, median event-free survival was 14.31 months (95% CI 9.30-22.31). Median overall survival and duration of CHR were not reached; median duration of CMR was 11.6 months. Most common treatment-emergent adverse events (TEAEs) were rash (36.4%), asthenia (22.7%), alanine transaminase increase (15.9%), erythema (15.9%), and γ-glutamyltransferase increase (15.9%). Cardiac and vascular TEAEs occurred in 29.5% (grade ≥3, 18.2%) and 27.3% (grade ≥3, 15.9%), respectively. Dose reductions, interruptions, and discontinuations due to TEAEs occurred in 43.2%, 43.2%, and 27.3% of patients, respectively; 5 patients had fatal TEAEs. Ponatinib and prednisone showed efficacy in unfit patients with Ph+ ALL; however, a lower ponatinib dose may be more appropriate in this population. This trial was registered at www.clinicaltrials.gov as #NCT01641107.

Combination of ponatinib and blinatumomab in Philadelphia chromosome-positive acute lymphoblastic leukemia: Early results from a phase II study.

7001 Background: Achievement of a complete molecular remission (CMR) is associated with superior outcomes in patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Ponatinib and blinatumomab both produce high rates of molecular remission in Ph+ ALL. The combination of these two agents may lead to durable responses and reduce the need for allogeneic hematopoietic stem cell transplant (AHSCT). Methods: This is a single-arm phase 2 study in adults with newly diagnosed (ND) or relapsed/refractory (R/R) Ph+ ALL. Patients received up to 5 cycles of blinatumomab as a continuous infusion at standard doses. Ponatinib 30mg daily was given during cycle 1. Ponatinib was decreased to 15mg daily once CMR was achieved. After completion of blinatumomab, ponatinib was continued for at least 5 years in responding patients. Twelve doses of prophylactic intrathecal chemotherapy were administered. For patients with ND Ph+ ALL, the primary endpoint was the CMR rate. For patients with R/R Ph+ ALL, the primary endpoint was the overall response rate (defined as the composite of CR/CRi). Results: Twenty-eight patients were treated (19 FL and 9 R/R). Median age was 59 years (range, 25-83 years); 62 years (range, 34-83 years) in the ND cohort and 36 years (range, 25-61 years) in the R/R cohort. Transcripts were p190 in 69% of patients the ND cohort and 100% in the R/R cohort. Among R/R patients, 44% were in Salvage 2+. No early death within 4 weeks were observed. Overall, 95% of patients responded; the response rate was 100% in the ND cohort and 88% in the R/R cohort. Among responding patients, 86% achieved CMR: 87% in the ND cohort and 86% in the R/R cohort. Median time to CMR was 1 month (range, 1-13 months). None of the patients in the ND cohort underwent AHSCT; 4 patients (44%) with R/R disease underwent subsequent AHSCT. With a median follow-up of 14 months, the estimated 1-year overall survival (OS) rate was 94% and event-free survival (EFS) rate was 81% for the entire study population. In the ND cohort, no patients have relapsed or died, and the 1-year OS and EFS rates were both 100%. In the R/R cohort, 1-year OS and EFS rates were 88% and 55%, respectively. The treatment was well-tolerated. Most side effects were grade 1-2. No patient discontinued ponatinib due to toxicity. One patient discontinued blinatumomab due to recurrent grade 2 tremor. Conclusions: The chemotherapy-free combination of ponatinib and blinatumomab shows encouraging results in Ph+ ALL. The regimen results in high rates of CMR and durable responses, potentially obviating the need for chemotherapy and AHSCT in many patients, particularly when used as frontline therapy. Clinical trial information: NCT03263572.

Clinical analysis of primary testicular diffuse large B-cell lymphoma

Objective To investigate the clinical features, diagnosis, treatment and prognosis of primary testicular diffuse large B-cell lymphoma (PT-DLBCL). Methods The clinical data of 2 patients with PT-DLBCL in the Second People's Hospital of Lianyungang treated in May 2013 and April 2018 was retrospectively analyzed. The clinical features, diagnosis, treatment and prognosis of PT-DLBCL were summarized with review of these 2 cases combining with other 42 cases reported in domestic literature. Results Case 1, a 71 years old man, complained of bilateral scrotal enlargement with pain and discomfort for 2 months. Case 2, an 85 years old man, presented with left scrotal mass for 3 months. All 2 patients underwent orchiectomy. Both of the 2 patients were diagnosed as PT-DLBCL and non-germinal center B-cell (non-GCB) subtype and had Ann Arbor stage ⅠE after operation. Case 1 received only 2 cycles of CHOP (cyclophosphamide, epirubicin, vincristine, prednisone) due to lack of financial support. Case 2 refused chemotherapy and right testis irradiation because of advanced age. They were followed up for 71 months and 12 months, respectively. They were both alive without recurrence at last time of the follow-up. The median age of 44 patients (2 cases in this study and 42 cases reported in the domestic literature) was 64 years old (range 45-87 years old). The most common symptom was unilateral painless testicular swelling (left testis 17 cases and right testis 24 cases). Twenty-one patients were Ann Arbor stage Ⅰ, 6 patients were stage Ⅱ, 6 patients were stage Ⅲ, and 11 patients were stage Ⅳ. Thirty-one patients were non-GCB subtype. Twelve patients were international prognostic index (IPI) score ≥3. Serum lactate dehydrogenase (LDH) level was elevated in 13 patients. All patients underwent orchiectomy. CHOP/R-CHOP chemotherapy was given to 40 patients and prophylactic radiation to contralateral testis was given to 12 patients. Twenty-two patients received prophylactic intrathecal chemotherapy. After a median follow-up of 17 months (range 3-135 months), 14 patients died and the median overall survival time was 13 months (range 3-96 months). Conclusions PT-DLBCL is rare. Its diagnosis mainly depends on pathology, with the majority of patients diagnosed in early Ann Arbor clinical stage and non-GCB subtype. The radical orchiectomy and R-CHOP chemotherapy is recommended due to local relapse and systemic dissemination. It is curable in the early stage while patients with advanced stage have a very poor prognosis. Prophylactic radiation to contralateral testis and intrathecal chemotherapy can decrease the risk of recurrence. Key words: Testicular neoplasms; Lymphoma, large B-cell, diffuse; Diagnosis; Treatment; Prognosis

Impact of prophylactic intrathecal chemotherapy on CNS relapse rates in AML patients presenting with hyperleukocytosis

Central nervous system (CNS) relapse in acute myeloid leukemia (AML) confers a poor prognosis. Despite the identification of risk factors for CNS relapse (e.g. hyperleukocytosis), there is no standard practice for CNS relapse risk reduction with intrathecal (IT) chemotherapy in patients. We compared outcomes of 50 patients who did not receive IT chemotherapy with 18 patients who did receive IT chemotherapy with a hyperleukocytosis at diagnosis (defined as white blood cell count ≥100,000 cells/mcL). There were three occurrences of CNS relapse, all within patients who did not receive prophylaxis. There was no difference in the incidence of CNS relapse between the patient cohorts (p = .560). These results highlight the low incidence of CNS relapse in our patient population that received and survived induction chemotherapy despite selecting for a high risk cohort. Furthermore, there is a need for a CNS relapse registry to standardize treatment approaches in this high-risk patient population.

Title: 12 Versus 8 Prophylactic Intrathecal (IT) Chemotherapy Administration Decrease Incidence of Central Nervous System (CNS) Relapse in Patients (pts) with Newly Diagnosed Philadelphia (Ph)-Positive Acute Lymphocytic Leukemia (ALL)

Introduction: The addition of tyrosine kinase inhibitors to hyperfractionated cyclophosphamide, dexamethasone, vincristine, and doxorubicin alternating with high-dose methotrexate and cytarabine (HCVAD) for the treatment of Ph-positive ALL has significantly improved outcomes. However, with the increased median survival, an increased incidence of CNS relapses were documented over time, thus suggesting an increased risk among pts with Ph-positive disease (Ravandi et al, Cancer 2015).In order to reduce this incidence, treatment protocols for Ph-positive ALL were amended in 2012 to increase prophylactic IT chemotherapy from 8 to 12 at our institution. The aim of this study is to compare the incidence of CNS relapses in pts with Ph-positive ALL treated with 8 versus 12 ITs. Methods: We conducted a retrospective chart review of 156 pts with newly diagnosed Ph-positive ALL treated with Rituximab (R)± HCVAD plus imatinib (n=35), dasatinib (n=68), or ponatinib (n=53) between July 2001 and January 2019. Pts with CNS disease at initial diagnosis were excluded. Complete molecular response (CMR) at 3 months was defined as absence of a quantifiable BCR-ABL1 transcript. CNS relapse was identified by detection of blasts or rare atypical cells in the cerebrospinal fluid (CSF) in at least 2 successive evaluations and/or findings of leptomeningeal disease on imaging. Landmark analysis was performed at 6 months at the approximate time of completion of both systemic and IT therapy. Poor risk cytogenetic abnormality was defined as the presence of +der(22)t(9;22) and/or −9/9p in the absence of high hyperdiploidy (51‐65 chromosomes). CNS relapse-free survival (RFS) was defined from the start of therapy to the time of CNS relapse. Patients who died or relapsed in bone marrow were censored at the time of death and systemic relapse, respectively. Survival was assessed with and without the censoring of allogeneic stem cell transplantation (ASCT). Results: Pt characteristics are summarized in Figure A. One hundred and twelve pts (72%) received a median of 8 ITs (range, 2-8) and 44 pts (28%) received a median of 12 (range, 9-15). There were no statistically significant differences between groups in regards to baseline characteristics with the exception that more patients in the &gt; 8 ITs cohort received ponatinib (66% vs 21%) and thus achieved a higher rate of 3-month CMR (70% vs 52%; p=0.04). CNS relapses were identified in 11 pts overall (7%, 4 treated with imatinib and 7 with dasatinib) and all of them received 8 or less prophylactic ITs (IT ≤8, 10% vs IT &gt;8, 0%; p=0.023). The median follow-up of the entire population was 81 months, and 97 and 43 months for pts who received ≤8 and &gt;8 ITs, respectively. The 3 and 6-year CNS RFS was 89% and 88% in pts with ≤8 ITs and 100% in pts with &gt;8 Its, respectively (overall P=0.041; 3-yr CNS RFS P=0.049; 6-yr CNS RFS P=0.045) (Figure B). The outcomes remained statistically significant even after censoring for ASCT (P=0.048) (Figure C). In a multivariate analysis and after adjusting for the follow-up time, a median of 12 prophylactic IT chemotherapies was a prognostic factor significantly associated with a decrease rate of CNS relapses (P=0.03; HR=0.64 95%, CI: 0.43-0.96) (Figure D). Conclusion: In pts with newly diagnosed Ph-positive ALL, incorporation of 12 prophylactic IT chemotherapy in addition to systemic therapy is a very effective strategy to reduce the long-term incidence of CNS relapses. Figure Disclosures Paul: Pfizer: Consultancy; Agios: Consultancy. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Kadia:BMS: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioline RX: Research Funding; Celgene: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Garcia-Manero:Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Amphivena: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Ravandi:Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding. Kantarjian:BMS: Research Funding; Novartis: Research Funding; AbbVie: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Research Funding; Daiichi-Sankyo: Research Funding; Takeda: Honoraria; Pfizer: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Astex: Research Funding; Jazz Pharma: Research Funding; Cyclacel: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding. Jabbour:AbbVie: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding.

CNS Prophylaxis in Diffuse Large B-Cell Lymphoma & Its Outcomes- an Institutional Review

Background: Diffuse large B-cell lymphoma (DLBCL) has an approximately 5% risk of recurrence in the central nervous system, and carries a very poor prognosis. Prophylactic intrathecal chemotherapy (ITC) with agents such as Methotrexate (MTX) can mitigate the risk of recurrence and improve survival. We report a single-institution, retrospective analysis of the effect of ITC administration on outcomes in patients with DLBCL, based on CNS-IPI risk stratification. Methods: We screened 325 DLBCL patients from our tumor registry- of these only 292 had clinical information to risk-stratify per IPI scoring- low-risk, n = 54, intermediate-risk, n = 198, and high-risk n = 40. These patients then further categorized based on the NCCN prognostic model to assess the risk of CNS disease (CNS-IPI) which includes age &gt;60, LDH &gt;normal, ECOG &gt;1, Stage III or IV, Extranodal involvement &gt;1 site, kidney or adrenal gland involvement with scores 0-1 low-risk, 2-3 intermediate-risk, and 4-6 or kidney or adrenal involvement as high-risk. The effect of ITC administration on outcomes such as overall survival (OS) at 1-year (yr) and 5-yr were calculated using univariate two-group comparisons. Results: Demographic and clinical variables include- Age &gt;60- 61% (n=201); mostly Caucasians- 71%(n=199); Germinal Center(GC) 25%(n=73), non-GC 74%(n=212); mean IPI score-2.8(n=196), R-CHOP-87%(n=233); and, ITC in 15%(n=45). Seven patients in low-risk patients received ITC for unclear reasons. Intermediate risk patients treated with ITC showed a trend towards 90% (n=26) 1yr OS, and 67%(n=8) 5-yr survival compared to who did not receive ITC (non-ITC) who had 84%(n=127) 1-yr, and 55%(n=52) 5-yr OS (p-value 0.57 and 0.43 respectively). High-risk patients treated with ITC showed a trend towards 100%(n=3) 1-yr, and 0% 5-yr OS compared to non-ITC who had 85%(n=23) 1-yr , and 29%(n=5) 5-yr OS (p-value 1.0 and 1.0 respectively). Conclusions: Our results suggest that in DLBCL patients with the intermediate-risk group may benefit from intrathecal chemotherapy. Our study is limited owing to small sample size in each subset of CNS risk stratification- this limits the interpretation of the results, and should be interpreted cautiously given nonsignificant P-values. However, we believe these results can encourage further research to evaluate the effect of CNS prophylaxis in the intermediate-risk group of DLBCL patients. Disclosures Kuriakose: Alexion: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy.

Long-Term Safety and Efficacy of Hyper-CVAD Plus Ponatinib As Frontline Therapy for Adults with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Long-Term Safety and Efficacy of Hyper-CVAD Plus Ponatinib As Frontline Therapy for Adults with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Systemic and prophylactic intrathecal chemotherapy for primary adrenal lymphoma: A retrospective study of 20 case reports.

Primary adrenal lymphoma (PAL) is a rare entity of lymphoma with dismal prognosis using systemic chemotherapy. More clinical reports are needed to guide the treatment for PAL.We performed a retrospective analysis of 20 patients diagnosed with PAL who presented to our center between January 2005 and January 2014.Median age at presentation was 48 years (range: 27–73) with a male-to-female ratio of 7:3. Bilateral and right-sided adrenal involvement were seen in 11 of 20 and 7 of 20 patients, respectively. Adrenal insufficiency (AI) was seen in 6 of 10 evaluated patients. Diffuse large B cell lymphoma (DLBCL) was the most common immunophenotype (85.0%). Two patients died due to rapid disease progression before treatment. Two patients received autologous stem cell transplantation as consolidation therapy. All patients received prophylactic intrathecal chemotherapy. The estimated 5-year overall survival (OS) and progression-free survival (PFS) were 52.5% [95% confidence interval (95% CI: 28.2–72.0)] and 53.2% (95% CI: 29.0–72.5), respectively.These findings suggest that PAL should always be considered in differential diagnosis of adrenal mass with AI. Despite the contrasting previous reports, long-term prognosis of PAL is not necessarily inferior to that of non-Hodgkin lymphoma in general.

Fluorodeoxyglucose Detected Changes in Brain Metabolism After Chemotherapy in Pediatric Non-Hodgkin Lymphoma

BackgroundPotential neurocognitive dysfunction after chemotherapy is a worrisome long-term outcome. Our objective was to evaluate the effect on brain metabolism in pediatric patients with non–central nervous system cancer treated with chemotherapy by analyzing brain data from serial whole-body fluorodeoxyglucose positron emission tomography/computed-tomography (FDG-PET/CT) scans taken before and sequentially after therapy. MethodsFourteen pediatric patients diagnosed with lymphoma and treated with systemic and prophylactic intrathecal chemotherapy were included. All patients had baseline pretreatment whole-body FDG-PET/CT and at least one post-therapy study preformed as part of standard surveillance. Brain positron emission tomography data were quantitatively analyzed for normalized fluorodeoxyglucose uptake in various brain regions. A generalized estimating equation approach was used to evaluate temporal changes after chemotherapy. ResultsMedian time of follow-up surveillance positron emission tomography–computed-tomography was 456 days after chemotherapy course. Various brain regions demonstrated significant changes in fluorodeoxyglucose uptake as a function of time passed since chemotherapy. Increased fluorodeoxyglucose uptake was noted in the parietal and cingulate cortexes. Decreased fluorodeoxyglucose uptake was demonstrated in deep gray matter nuclei and in the brainstem. ConclusionsOur study provides novel insights into long-standing and progressive changes in regional glucose metabolism after chemotherapy in pediatric cancer population, lasting long after the end of therapy and reaching clinical remission. Expanding the utility of regular surveillance fluorodeoxyglucose positron emission tomography to a detailed quantitative assessment of regional brain metabolism after chemotherapy can provide valuable information on individual chemotherapy-related neuromodulation and facilitate the development of strategies to minimize neurocognitive side effects.

Primary breast diffuse large B‐cell lymphoma in the rituximab era: Therapeutic strategies and patterns of failure

Primary breast diffuse large B‐cell lymphoma (PB‐DLBCL) is a rare subtype of DLBCL with limited data on patterns of failure. This multicenter study aimed to define the optimum treatment strategy and patterns of failure for PB‐DLBCL patients. We retrospectively reviewed data on 108 PB‐DLBCL patients from 21 Chinese medical centers. Only patients with localized disease (involvement of breast and localized lymph nodes) were included. After a median follow‐up of 3.2 years, 32% of patients developed progression or relapse. A continuous pattern of relapse was observed, characterized by frequent late relapses in the contralateral breast and central nervous system (CNS). Although rituximab significantly reduced the overall cumulative risk of progression or relapse (5‐year cumulative risk 57% vs 24%, P = .029), it had limited effect on the reduction of breast relapse (P = .46). Consolidative radiotherapy significantly decreased the risk of breast relapse, even in the subgroup of patients treated with rituximab (5‐year cumulative risk 21.2% vs 0%, P = .012). A continuous risk of CNS progression or relapse up to 8.2 years from diagnosis was observed (10‐year cumulative risk 28.3%), with a median time to CNS relapse of 3.1 years. Neither rituximab nor prophylactic intrathecal chemotherapy significantly decreased the risk of CNS relapse. In summary, our study indicates that PB‐DLBCL has a continuous pattern of relapse, especially with frequent late relapses in the CNS and contralateral breast. Rituximab and RT confer complementary benefit in the reduction of relapse. However, neither the addition of rituximab nor prophylactic intrathecal chemotherapy could effectively prevent CNS relapse for PB‐DLBCL patients.

Prolonged Survival of Acute Lymphoblastic Leukemia with Intrathecal Treatments for Isolated Central Nervous System Relapse

Acute lymphoblastic leukemia is commonly cured when diagnosed in the pediatric population. It portends a poorer prognosis if present in adult patients. Although adults frequently achieve complete remission, relapse rates are substantial, particularly among the elderly and high-risk populations. In the absence of prophylactic intrathecal chemotherapy, more than half of patients may develop CNS involvement or relapse, which is associated with significant risk for systemic illness. This report describes a patient with acute lymphoblastic leukemia with repeated isolated CNS relapses. This case should remind clinicians that isolated CNS disease in the absence of systemic recurrence could successfully respond to intrathecal therapy and offer patients a favorable quality of life.