Leukemia Group Research Articles

Wedge resection, segmentectomy, and lobectomy: oncologic outcomes based on extent of surgical resection for ≤2 cm stage IA non-small cell lung cancer.

Long-standing controversy has existed over whether sublobar resection is an adequate oncological procedure for clinical stage IA non-small cell lung cancer (NSCLC) ≤2 cm, despite the recent randomized trial reports of Japanese Clinical Oncology Group (JCOG) 0802 and Cancer and Leukemia Group B (CALGB) 140503 demonstrating non-inferior outcomes with sublobar resection compared to lobectomy. As practice patterns shift, we sought to compare oncologic outcomes in patients with these early-stage tumors after wedge resection, segmentectomy, or lobectomy in a contemporary, real-world, cohort. A retrospective review of a prospectively maintained database from a single institution was conducted from 2011 to 2020 to identify all patients with clinically staged IA1 or IA2 NSCLC (tumors ≤2 cm with no nodal involvement). The primary outcomes of interest were overall survival (OS) and disease-free survival (DFS), with secondary outcomes of lung cancer-specific survival (LCSS), recurrence patterns, and perioperative morbidity and mortality. A total of 480 patients were identified; 93 (19.4%) patients underwent wedge resection, 90 (18.7%) received segmentectomy, and 297 (61.9%) underwent lobectomy. Patients who underwent wedge resection had worse Eastern Cooperative Oncology Group (ECOG) performance status (23.7% ECOG 1 or 2 vs. 5.6% among segmentectomy and 5.4% among lobectomy, P<0.05). Both wedge resection and segmentectomy patients had lower preoperative mean percentage of predicted forced expiratory volume in one second (%FEV1) compared to the lobectomy group (81.8% and 82.6% vs. 89.6%, P=0.002), a higher proportion of patients with chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD), and a higher Charlson Comorbidity Index. There were no statistically significant differences in 5-year OS, DFS, or LCSS between groups: 90%, 61%, 78% for wedge resections compared with 85%, 75%, 86% for segmentectomy, and 87%, 77%, 87% for lobectomy, respectively. Recurrence was observed in 17 patients who underwent wedge resection (18.3%, 8 local, 9 distant), 12 patients who received segmentectomy (13.4%, 6 local, 6 distant), and 38 patients who underwent lobectomy (12.8%, 11 local, 27 distant), which was not significantly different (P=0.36). Patients with inferior performance status or lower baseline pulmonary function are more likely to receive wedge resection for clinical stage IA NSCLC ≤2 cm in size. For these small tumors, lobectomy, segmentectomy, and wedge resection provide comparable oncologic outcomes.

Toll-Like Receptor 4, 2, and Interleukin 1 Receptor Associated Kinase4: Possible Diagnostic Biomarkers in Myelodysplastic Syndrome Patients.

Myelodysplastic syndrome (MDS) is a clonal hematologic disorder that requires the integration of morphologic, cytogenetic, hematologic, and clinical findings for a successful diagnosis. Trying to find ancillary tests such as biomarkers improve the diagnosis process. Several studies showed that a disordered immune system is associated with MDS. The chronic activated innate immune system, particularly the Toll-like receptors (TLRs) pathway could be involved in the induction of the inflammation. In the present study, we investigated the expression of TLR2, TLR4, and IRAK4 in bone marrow (BM) of MDS patients, the leukemia group, and the healthy group. For this purpose, we assessed the expression of TLR2, TLR4, and IRAK4 by real time-PCR. In line with new findings, we demonstrated that the expression of TLR2, TLR4, and IRAK4 significantly increased in MDS BM compared with the healthy group. Moreover, IRAK4 expression raised significantly in MDS patients compared with other studied hematologic neoplasms. Also, the expression levels of TLR2 and TLR4 significantly increased in MDS in comparison to some studied non-MDS malignancies (P ˂ 0.05). Receiver operating characteristics (ROC) analysis and area under the curve (AUC) suggested that the expression of TLR2, TLR4, and IRAK4 (AUC = 0.702, AUC = 0.75, and AUC = 0.682, respectively) had acceptable diagnostic values to identify MDS from the other understudied leukemias. Overall, the expression of TLR2, TLR4, and IRAK4 could be potential biomarkers for discriminating MDS from some hematologic disorders.

Long-term neurotoxicity among childhood acute lymphoblastic leukaemia survivors enrolled between 1971 and 1998 in EORTC Children Leukemia Group studies

Survival after childhood acute lymphoblastic leukemia (ALL) has increased over the last 40 years with an overall survival above 90%. Survivors may experience neurological late effects secondary to chemotherapy and radiotherapy. This observational retrospective study evaluated the cumulative incidence of neurological late effects among 890 childhood ALL survivors treated in EORTC CLG trials (58741, 58831/2 and 58881) between 1971 and 1998. Median follow-up was 19 years and interquartile range of the follow-up was 15–22 years. At 20 years from the end of treatment, approximately 66% of patients from the 58741 trial (accrual time: 1971–1978) and approximately 15% from the more recent trials had cognitive disturbance grade 1 or higher. Cumulative incidences at 20 years from treatment end of seizures, stroke and leukoencephalopathy were respectively 45%, 16% and 62% in study 58741, 13%, 2% and 5% in study 58831/2, and 8%, 2% and 3% in study 58881. Patients who were 10–17 years of age at diagnosis had a higher incidence of stroke and leukoencephalopathy as compared to those less than 6 years of age. Noteworthy, all neurological late effects continued to occur beyond 5 years after end of treatment. This retrospective study highlights the frequency of neurological late effects in survivors of childhood ALL. With the increase of the overall survival of ALL patients, the role and potential benefit of longitudinal neurological screening should be evaluated in further studies as these neurological late effects become an important public health challenge. This study is part of the larger EORTC CLG 58 Late Adverse Effects (LAE) study (ClinicalTrials.gov Identifier NCT01298388, date of registration February 16, 2011).

Carfilzomib, thalidomide, and dexamethasone are safe and effective in relapsed and/or refractory multiple myeloma: final report of the single-arm, multicenter, phase II ALLG MM018/AMN002 study.

This multicenter, phase II study of the Australasian Lymphoma and Leukemia Group and the Asian Myeloma Network investigated fixed-duration (18-month) treatment with carfilzomib (K), thalidomide (T), and dexamethasone (d) (KTd) in patients with relapsed and/or refractory multiple myeloma who had received one to three prior lines of therapy. Patients received induction with up to 12 28-day cycles of carfilzomib (20 mg/m2 intravenously in cycle 1 on days 1 and 2, then 56 mg/m2 [36 mg/m2 for patients ≥75 years] from day 8 onwards), thalidomide 100 mg orally in the evening and weekly dexamethasone 40 mg (20 mg for patients ≥75 years). During maintenance, thalidomide was omitted, while carfilzomib was continued on days 1, 2, 15, and 16 with fortnightly dexamethasone. The primary endpoint was progression-free survival. Secondary endpoints were overall response rate, overall survival, duration of response, safety, and tolerability. Ninety-three patients (median age 66.3 years [range, 41.9-84.5]) were enrolled and followed up for a median of 26.4 months (range, 1.6-54.6). The median progression-free survival was 22.3 months (95% confidence interval: 15.7-25.6) and the 2-year progression-free survival was 46.3% (95% confidence interval: 35.1-52.8). The median overall survival was not reached and the 2-year overall survival was 73.8% (95% confidence interval: 62.9-81.9). The overall response rate was 88% (73% had a very good partial response or better). There was no difference in the depth of response, progression-free survival or overall survival comparing Asian and non-Asian cohorts (P=0.61). The safety profile of KTd was consistent with that of each individual drug. KTd is well tolerated and effective in patients with relapsed and/or refractory multiple myeloma irrespective of Asian or non-Asian ethnicity and provides an alternative treatment option, particularly in circumstances in which the use of carfilzomib, lenalidomide, and dexamethasone (KRd) is limited by access, cost, or renal impairment.

Gemtuzumab Ozogamicin in Acute Myeloid Leukemia: Efficacy, Toxicity, and Resistance Mechanisms-A Systematic Review.

Acute myeloid leukemia (AML) is a diverse group of leukemias characterized by the uncontrolled proliferation of clonal neoplastic hematopoietic precursor cells with chromosomal rearrangements and multiple gene mutations and the impairment of normal hematopoiesis. Current efforts to improve AML outcomes have focused on developing targeted therapies that may allow for improved antileukemic effects while reducing toxicity significantly. Gemtuzumab ozogamicin (GO) is one of the most thoroughly studied molecularly targeted therapies in adults. GO is a monoclonal antibody against CD33 IgG4 linked to the cytotoxic drug calicheamicin DMH. The use of GO as a chemotherapeutic agent is not generalized for all patients who suffer from AML, particularly for those whose health prevents them from using intensive conventional chemotherapy, in which case it can be used on its own, and those who have suffered a first relapse, where its combination with other chemotherapeutic agents is possible. This systematic review aimed to comprehensively evaluate GO, focusing on its molecular structure, mode of action, pharmacokinetics, recommended dosage, resistance mechanisms, and associated toxicities to provide valuable information on the potential benefits and risks associated with its clinical use. A systematic review of eight scientific articles from 2018 to 2023 was conducted using PRISMA analysis. The results showed that GO treatment activates proapoptotic pathways and induces double-strand breaks, initiating DNA repair mechanisms. Cells defective in DNA repair pathways are susceptible to GO cytotoxicity. GO has recommended doses for newly diagnosed CD33+ AML in combination or as a single agent. Depending on the treatment regimen and patient status, GO doses vary for induction, consolidation, and continuation cycles. Multidrug resistance (MDR) involving P-glycoprotein (P-gp) is associated with GO resistance. The overexpression of P-gp reduces GO cytotoxicity; inhibitors of P-gp can restore sensitivity. Mitochondrial pathway activation and survival signaling pathways are linked to GO resistance. Other resistance mechanisms include altered pharmacokinetics, reduced binding ability, and anti-apoptotic mechanisms. GO has limited extramedullary toxicity compared to other AML treatments and may cause hepatic veno-occlusive disease (HVOD). The incidence of hepatic HVOD after GO therapy is higher in patients with high tumor burden. Hematological side effects and hepatotoxicity are prominent, with thrombocytopenia and neutropenia observed. In conclusion, GO's reintroduction in 2017 followed a thorough FDA review considering its altered dose, dosing schedule, and target population. The drug's mechanism involves CD33 targeting and calicheamicin-induced DNA damage, leading to apoptosis and resistance mechanisms, including MDR and survival signaling, which impact treatment outcomes. Despite limited extramedullary toxicity, GO is associated with hematological side effects and hepatotoxicity.

CCR5 and CCL5 gene expression in colorectal cancer: comprehensive profiling and clinical value

BackgroundThe C-C motif chemokine receptor 5 (CCR5)/C-C motif chemokine ligand 5 (CCL5) axis plays a major role in colorectal cancer (CRC). We aimed to characterize the molecular features associated with...

Characteristics and outcomes of patients with lymphoma who developed therapy-related acute myeloid leukemia or myelodysplastic syndrome - a retrospective analysis of the Polish Adult Leukemia Group.

Enhancing lymphoma outcomes increases the risk of therapy-related neoplasms such as acute myeloid leukemia (t-AML) and myelodysplastic syndrome (t-MDS). Our study, conducted at seven Polish hematology centers between 2011 and 2018, explores clinical features, outcomes, and prognostic factors of t-AML and t-MDS arising after initial lymphoid neoplasms. The analysis included 57 patients of median age 65 with t-MDS (n = 38) and t-AML (n = 19). The median time to the onset of t-MDS/AML was 58.7 months. The median overall survival (OS) was 16.1 months. The presence of unfavorable cytogenetics and molecular risk factors (HR 2.88, 95% CI: 1.29-6.42, p = 0.009), hemoglobin level (HR 0.79, 95% CI: 0.65-0.95, p = 0.01) and platelets (HR 0.99, 95% CI: 0.99-0.9996, p = 0.03) were independent prognostic factors influencing OS. Therapy- related myelodysplastic syndrome/acute myeloid leukemia after lymphoma treatment is associated with a dismal prognosis mainly due to poor cytogenetic risk. Anemia and thrombocytopenia may indicate more severe impairment of bone marrow function, resulting in further inferior treatment outcomes.

Gemtuzumab ozogamicin for relapsed or primary refractory acute myeloid leukemia in children-the Polish Pediatric Leukemia and Lymphoma Study Group experience.

Gemtuzumab ozogamicin (GO), one of the first targeted drugs used in oncology, consists of an anti-cluster of differentiation 33 (CD33) monoclonal antibody bound to a derivative of cytotoxic calicheamicin. After the drug withdrawn in 2010 due to a significantly higher rate of early deaths, GO regained approval in 2017 for the treatment of newly diagnosed, refractory, or relapsed acute myeloid leukemia (AML) in adults and children over 15 years of age. The objective of the study was a retrospective analysis of clinical characteristics, treatment outcomes, and GO toxicity profile in children with primary refractory or relapsed (R/R) AML treated in Poland from 2008 to 2022. Data were collected through the Polish Registry of Acute Myeloid Leukemia. From January 2008 to December 2022, 35 children with R/R AML were treated with GO in seven centers of the Polish Pediatric Leukemia and Lymphoma Study Group. Most of the children (30 of 35) received only one GO cycle in combination with various chemotherapy cycles (IDA-FLA, DOXO-FLA, FLA, FLAG, and others). Eighteen children (51%) achieved complete remission (CR), 14 did not respond to treatment, and three progressed. GO therapy was followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 18 children in CR. The 5-year overall survival (OS) after GO therapy was 37.1% ± 8.7% for the total cohort. There was a trend toward a superior outcome in patients with strong expression of CD33 expression (over 50% positive cells) compared with that in patients with lower expression of CD33 (OS, 41.2% ± 11.9% versus 27.8% ± 13.2%; p = 0.5; 5-year event-free survival, 35.4% ± 11.6% versus 25.7% ± 12.3%; p = 0.5, respectively). Children under 15 years have better outcome (OS, 34.9% ± 10.4% versus 30% ± 14.5%, p = 0.3). The most common adverse events were bone marrow aplasia, fever of unknown origin, infections, and elevated liver enzyme elevation. Sinusoidal obstruction syndrome occurred in two children. The use of GO in severely pretreated children, including those under 15 years of age, with previous failure of AML treatment is a feasible and effective bridging therapy to allo-HSCT with an acceptable toxicity profile.

Association of PIK3CA Mutation With Pathologic Complete Response and Outcome by Hormone Receptor Status and Intrinsic Subtype in Early-Stage ERBB2/HER2-Positive Breast Cancer

PIK3CA mutations may be associated with outcomes of patients with ERBB2/HER2-positive early breast cancer (EBC). To assess if PIK3CA mutations among patients with ERBB2/HER2-positive EBC are associated with treatment response and outcome, and if these associations vary by hormone receptor (HR) status or intrinsic molecular subtype (IMS). This cohort study derived data on 184 patients from the phase 3 neoadjuvant Cancer and Leukemia Group B (CALGB) 40601 trial that enrolled patients with ERBB2/HER2-positive EBC in North America between January 1, 2008, and December 31, 2012. Participants received neoadjuvant paclitaxel with trastuzumab, lapatinib, or both. Statistical analysis was performed from March 23, 2022, to March 9, 2023. Gene expression profiling by RNA sequencing with Prediction Analysis of Microarray 50-determined IMS and PIK3CA mutations from whole-exome sequencing were obtained from pretreatment biopsies from 184 of 305 trial participants. The primary end point was pathologic complete response (pCR) and the secondary end point of event-free survival (EFS). The association of PIK3CA mutations with pCR and EFS by HR status and IMS was estimated using logistic and Cox proportional hazards regression models. All 184 participants were women, with a median age of 49 years (range 24-75 years). A total of 121 participants (66%) had clinical stage II tumors; 32 (17%) had PIK3CA mutations, most frequently H1047R (38% [12 of 32]) and E545K (22% [7 of 32]). PIK3CA mutations were present in 20 of 102 cases of HR-positive EBC (20%) and 12 of 82 cases HR-negative EBC (15%) and varied by IMS (luminal B, 9 of 25 [36%]; luminal A, 2 of 21 [10%]; and ERBB2/HER2-enriched tumors, 19 of 102 [19%]). Pathologic complete response rates were lower in PIK3CA mutated than PIK3CA wild type in the overall population (34% [11 of 32] vs 49% [74 of 152]; P = .14) and were significantly different among those receiving trastuzumab (30% [7 of 23] vs 54% [63 of 117]; P = .045). At a median follow-up of 9 years, PIK3CA mutations were significantly associated with worse EFS in the overall cohort (hazard ratio, 2.58 [95% CI, 1.24-5.35]; P = .01), which persisted in a multivariable model including pCR, HR status, stage, and IMS (hazard ratio, 2.52 [95% CI, 1.16-5.47]; P = .02). The negative association of PIK3CA mutation was significant in HR-positive (hazard ratio, 3.60 [95% CI, 1.45-8.96]; P = .006) and luminal subtypes (hazard ratio, 4.84 [95% CI, 1.08-21.70]; P = .04), but not in nonluminal and HR-negative tumors. In ERBB2/HER2-positive EBC, PIK3CA mutations were associated with lower pCR rates and independently associated with worse long-term EFS. These findings appear to be associated with PIK3CA mutations in HR-positive and luminal EBC.

BRAF-Mutated Acute Myeloid Leukemia (AML) Represents a Distinct, Prognostically Poor Subgroup Enriched in Myelodysplasia-Related (MR-)AML

Background RAS signaling pathway mutations, mainly NRAS, KRAS, and/or PTPN11 variants, are common somatic events in de novo and MR-AML. BRAF mutations occur with lower frequency in AML and are reported to be associated with poor treatment outcome. However, no comprehensive analysis exists that firmly delineates clinical and molecular characteristics of BRAF-mutated AML, including insights into clonal architecture and co-occurring mutations. Methods We identified 42 patients (pts) with BRAF-mutated AML among pts with molecularly profiled disease in the setting of large comprehensive cancer centers [enriched for relapsed/refractory (R/R) and secondary AML] and cooperative group frontline trials (Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology, enriched for de novo AML). All pts had NGS-based targeted sequencing data, cytogenetic information, and detailed clinical annotations available. To fully evaluate the molecular landscape, 6 pts underwent integrated genomic profiling including paired tumor/normal whole exome sequencing and total transcriptome sequencing. We also analyzed pt samples using simultaneous single-cell molecular profiling and cell surface protein expression (DNA+Protein) sequencing to assess cell states and clonal make-up at single-cell resolution in a subset of pts (n=8). Results The 42 pts with BRAF-mutated AML had a median age of 67 years (range, 19-84); 57% were male. BRAF mutations were most common in cases of MR-AML (as defined by WHO 5th edition), accounting for 32 (76%) pts. BRAF mutations were found in newly diagnosed (n=19, 45%), R/R (n=8, 19%) and secondary AML (n=15, 36%) pts. As detected by bulk NGS sequencing, BRAF mutations were found both as dominant clonal and subclonal events, present at variant allele fractions (VAF) of 1-83% ( Figure 1, BRAF VAF indicated via color scale). Most (n=30, 71%) pts had non-V600 BRAF mutations (including G469, n=12; D594, n=7 and other, n=12). The most frequent co-occurring mutations were in the TET2 (36%), ASXL1 (33%), NRAS (29%), KRAS (26%), RUNX1 (19%), DNMT3A, FLT3-ITD/TKD, NPM1 and SRSF2 (all 17%) genes. By whole exome sequencing, BRAF-mutated AML samples carried a median mutational burden of 15 non-synonymous coding variants (range, 9-30), including 6 RAS-pathway and 3 MR-AML mutations. In 2 pts with paired relapse material available, the BRAF mutation was either stable at relapse or lost and the pt instead acquired a IQGAP3 mutation, supporting the RAS-pathway “addiction” of this leukemia. Single-cell multi-omic sequencing studies uncovering unique genotype-immunophenotype relationships and confirming clonal hierarchies are ongoing and will be presented at the meeting. Clinically, the BRAF-mutated pts had extremely poor survival, regardless of therapy. Pts were treated with low intensity [LI, n=10 (29%); LI+venetoclax (VEN, n=10 (29%)], high-intensity [HI, n=12 (34%) or HI+VEN, n=3 (9%)] regimens. The overall composite remission (CR+CRi) rate was 39%. Median overall survival (OS) for the entire cohort was 7 months, with 31 (89%) of pts deceased at the time of last follow-up. There were no significant differences in OS based on treatment regimens ( Figure 2). Importantly, there was no impact of BRAF variant allele burden on OS, with pts wiith dominant clonal and those with subclonal mutations having similar outcomes. Given the enrichment of BRAF mutations in MR-AML, we assessed whether RAS pathway mutations generally represented poor outcome prognosticators in this subgroup. A comparison of a control cohort of MR-AML pts with (n=129) and without (n=403) RAS pathway mutations treated on cytarabine/daunorubicin-based frontline protocols, revealed no survival difference between RAS-mutated and wild-type pts, suggesting a negative survival impact specific to BRAF-carrying leukemic clones. Conclusions BRAF mutations are rare, but recurrent molecular alterations in AML that are enriched in MR-AML. They associate with distinctly poor prognosis regardless of their clonal burden, without significant therapeutic advantage of currently available treatment regimens. This suggests the need to assess the utility of BRAF inhibitors and/or RAS pathway-targeting regimens such as MEK inhibitors in pts with AML carrying BRAF mutations. Support: U10CA180821, U10CA180882, U24CA196171; Clinicaltrials.gov: NCT00048958 (CALGB 8461), NCT00899223 (CALGB 9665), NCT00900224 (CALGB 20202)

Characterization of Comparative Clinical Outcomes and Molecular Features of Black Patients with Acute Promyelocytic Leukemia (APL) Reveals Similar Survival and Distinct Genomic Profiles

Introduction: Although APL, a subtype of acute myeloid leukemia (AML), is an aggressive disease, its treatment was revolutionized with combination all- trans retinoic acid (ATRA) and arsenic trioxide (ATO), making APL a highly curable malignancy. Molecularly, APL is characterized by t(15;17) resulting in PML:: RARA gene fusion as disease-initiating event and by several recurrent gene mutations (eg, FLT3) identified in previous studies. In AML, prior studies have established inferior overall survival (OS) of Black versus White AML patients (pts) in both population-based analyses and clinical trials, found a negative prognostic impact of higher social deprivation (SDI), and characterized differences in frequencies and impact of disease-associated gene mutations. Herein, we compared OS of Black and White APL pts and evaluated genomic landscape of Black pts, which has not been comprehensively assessed to date. Methods: For nationwide population analysis, 2 sets of cancer registries were included in the Surveillance Epidemiology End Results (SEER) Program of the National Cancer Institute to identify 829 adults diagnosed with de novo APL (confirmed by cytogenetic and/or molecular findings) in 1995-2019. To assess survival in the setting of clinical trials, we analyzed 249 pts treated on historic frontline Cancer and Leukemia Group B (CALGB)/Alliance for Clinical Trials in Oncology (Alliance) trials with or without inclusion of ATRA (CALGB 9191, 1992-1995; CALGB 9710, 1999-2005). For Alliance pts, neighborhood SDI was assigned based on pt-reported residence zip code and classified as low (1-25, n=33) or high deprivation (26-100, n=95). OS was analyzed separately for pts diagnosed before and after 2012 to account for treatment advances with ATRA/ATO. To assess molecular features, we performed integrated genomic profiling (paired tumor/normal whole-exome and transcriptome sequencing) on 31 Black APL Alliance pts (9/31 completed, with complete results to be presented at the Annual Meeting). Results: On a population level using SEER data, 3-year (3y) OS significantly improved from 65% for cases diagnosed in 1995-2012 to 75% in those diagnosed after 2012 (p=&amp;lt;0.001), concordant with ATRA/ATO use. Notably, OS of Black and White pts did not differ significantly before or after 2012. This held true in race-specific findings for median household income, Yost index and urban/rural status; none of which significantly associated with OS. Older age was the only parameter associated with OS (3y rates, 1995-2012: &amp;lt;40y, 79%; 40-59y, 71%; ≥60y, 44%; and 2012-2019: &amp;lt;40y, 92%; 40-59y, 80%; ≥60y, 56%). Again, OS of Black and White pts did not differ within age groups. Likewise, OS of Black and White APL pts treated in a relatively controlled setting of clinical trials was not significantly different. As in population-based findings, OS improved over time and with ATRA addition (3y OS rates, 1992-1995, 66%; 1999-2005, 85%), and older age was a strong negative OS predictor (p&amp;lt;0.001). When comparing OS of pts treated on clinical trials with population-based OS, trial pts had a longer 3y OS (84% vs 64%, p&amp;lt;0.001). Notably, pts with SDI &amp;gt;25 (n=95) had a worse OS than pts with SDI &amp;lt;25 (n=33, p=0.03). On a molecular level, preliminary results of whole-exome sequencing (finalized for 9/31 Black pts) showed frequent mutations in FLT3 (5/9 pts), a known APL-associated event, but also revealed several recurrent gene mutations not reported in prior APL sequencing efforts, which were almost exclusively based on White pts, including mutations in DPP6, GOLA6L, NLGN2 and SP8 (found in ≥2 pts). Intriguingly, CALR mutations were found in 3/9 pts. Mutations in FLT3 and CALR were mutually exclusive and found in 8/9 pts, with the remaining pt harboring a SORBS2 mutation. Conclusions: In contrast to most cancer types, including AML, there was no OS disparity with respect to race in APL pts, both in population-based analyses and in the setting of historic clinical trials. Older age and residence with high SDI (&amp;gt;25) were negative OS predictors. Molecularly, our pilot data reveal existence of ancestry-associated differences in driver mutations, suggesting that FLT3 and CALR mutations represent necessary proliferative signals in addition to PML:: RARA-driven differentiation arrest. Support: U10CA180821, U10CA180882, U24CA196171; Clinicaltrials.gov IDs: NCT00048958, NCT00899223, NCT00900224; https://acknowledgments.alliancefound.org

Retrospective Analysis of Adolescent Young Adult Patients with Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma Treated with the CALGB 10403 Regimen Since Completion of Trial Enrollment

INTRODUCTION The outcomes of adolescent and young adult (AYA) patients (ages 15-39 years) with acute lymphoblastic leukemia/lymphoma (ALL) have improved in part with the adoption of pediatric ALL regimens in the adult treatment setting. The Cancer and Leukemia Group B (CALGB) 10403 trial (C10403) was the largest prospective trial conducted in the United States (U.S.), demonstrating the safety and efficacy of delivering an intensive pediatric regimen utilizing asparaginase in the adult oncology treatment setting to AYAs with ALL, with 3-year event-free survival (EFS) and overall survival (OS) of 59% (95% CI, 54%-65%) and 73% (95% CI, 68%-78%), respectively (Stock et al., Blood 2019). Although this regimen is widely used in the U.S., outcomes for patients treated with C10403 outside of a clinical trial setting remain unknown. We thus conducted a multi-center retrospective study to examine the real-world, off-trial efficacy of the C10403 regimen delivered across U.S. cancer centers. METHODS AYAs ages 17-40 years with newly diagnosed Ph-neg B-ALL or T-ALL between October 1, 2012 and July 1, 2020 who received initial treatment with the C10403 regimen (off trial) across 5 U.S. centers were included. Patients were excluded if they had Ph+ or Burkitt-type ALL. Previously treated patients, except with hydroxyurea, steroids, or one dose of single-agent therapy were excluded; patients given rituximab for CD20+ B-ALL were included. Primary endpoints were induction response rate (IRR), 3-year EFS, and 3-year OS. Induction response was defined as achieving &amp;lt;5% blasts on bone marrow by end of induction or extended induction. Patients were censored for EFS at the time of change in regimen, the addition of another agent (eg blinatumomab) or if they proceeded to hematopoietic cell transplant (HCT). Patients with deviation from the C10403 regimen were included in the 3-year OS analysis. Events were defined as: 1) failure to achieve bone marrow response by the end of induction or extended induction, 2) failure to achieve metabolic response of lymphoma on PET-CT as determined by the clinician 3) death, 4) relapse at any site, or 5) development of second malignancy. RESULTS Among 101 included in the cohort, 54% were 20-29 years old, 69% were male, 55% were Caucasian and 31% identified as Hispanic. Of those with B-cell immunophenotype (70%), 49% had CD20 expression. The majority had normal karyotype (40%), while 3% were hypodiploid, 7% were KMT2a-rearranged, and 30% of the 27 patients assessed had Ph-like ALL. CNS involvement at diagnosis was documented in 20% (9% CNS2/11% CNS3) and 14% had a mediastinal mass. Of the B-ALL cohort (N=71), 16 (23%) received at least one dose of rituximab. Among the entire cohort, the IRR was 91% (54% MRD negative; threshold of at least 10 -4). Of the 101 patients who began induction with C10403, 72 (71%) completed induction and continued to consolidation; 51 (50%) continued beyond consolidation, and 31 (31%) completed the entire C10403 regimen through end of maintenance. Two patients (2%) died while in remission and still receiving treatment. Forty-four patients (44%) were taken off C10403 while in CR; 20 (20%) for allogeneic HCT, 23 (23%) for non-HCT alternative treatments including Hyper-CVAD or blinatumomab, and 1 (1%) for patient preference. The 3-year EFS and OS were 65% (95% CI, 53.8%-78.5%) and 82.7% (95% CI, 75.5%-90.5%), respectively (Figures 1 and 2). Conclusion In this multi-center, real world study of the C10403 regimen administered to newly diagnosed AYA ALL patients across adult U.S. centers, we demonstrate survival outcomes as favorable as the reported clinical trial results. While only 31% of patients completed the regimen through end of maintenance, a majority of patients who came off regimen either underwent consolidative HCT or alternative therapy while in CR. These data confirm the pediatric regimen as an excellent front-line option in AYA ALL.

A Meta-Analysis Comparing the Relative Efficacy of Pediatric-Inspired Regimens Versus Hyper-CVAD for the Treatment of Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma in Adolescents, Young Adults, and Adults

Background: Acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL)are rare aggressive hematologic malignancies. Children with ALL/LBL have an overall favorable prognosis; however, adult patients (pts) have a poorer outcome. As a result, pediatric or pediatric-inspired regimens with asparaginase (ASP) have been used in adolescents and young adult (AYA) pts with ALL/LBL with promising results. Unfortunately, there are no prospective randomized studies comparing this approach with hyper-CVAD, a commonly used adult regimen not containing ASP. A meta-analysis was conducted to assess the efficacy of pediatric-inspired ASP-containing regimens compared with hyper-CVAD in treating ALL/LBL in AYA and adult pts. Methods: We performed a systematic literature review (using databases including PubMed, Embase, and Cochrane Library) to identify relevant studies comparing ASP-containing regimens and hyper-CVAD in pts with ALL/LBL published up to April 21, 2022. The search strategy consisted of title/abstract key words and subject headings describing key concepts of “acute lymphoblastic leukemia,” “lymphoblastic lymphoma,” “asparaginase,” “hyper-CVAD,” “refractory,” and “minimal residual disease.” Abstracts were screened for inclusion to identify full texts that were assessed for eligibility. To determine the effects of intervention on complete response (CR) and overall survival (OS) (2 commonly reported outcomes across identified studies), odds ratios (OR) and hazard ratios (HR) were calculated. A meta-analysis was conducted using both random- and fixed-effects models to estimate the pooled OR and HR, 95% confidence intervals (CIs), and 95% prediction intervals (PIs). Scenario analyses identified potential sources of heterogeneity and bias. Results: The initial search identified 46 primary publications of potential relevance: 12 studies directly compared ASP-containing regimens and hyper-CVAD, but none were randomized. Based on direct comparison studies, ASP-containing regimens had statistically significant improvement in median OS (4 studies), 2-year OS (1 study), 3-year OS (3 studies), and 5-year OS (1 study) compared with hyper-CVAD. Four studies with comparable demographics were suitable for meta-analysis (n=702 total pts; n=366 ASP-containing regimens; n=336 hyper-CVAD): 2 studies in AYA (aged 13-43 yrs) and 2 in adults of any age (aged &amp;gt;16 yrs). ASP-containing regimens in the included studies were all based on Berlin-Frankfurt-Münster (BFM) or Cancer and Leukemia Group B (CALGB)-10403 protocols. Pts treated with ASP-containing regimens had a significantly higher chance of achieving CR (random- and fixed-effects model: OR, 2.04 [95% CI: 1.31, 3.18]) and improved OS (random-effects model: HR, 1.76 [95% CI: 1.36, 2.29]; fixed-effects model: HR, 1.75 [95% CI: 1.36, 2.24]) than those treated with hyper-CVAD. There was a low level of heterogeneity among studies for both CR (I 2=0%, tau^2=0.00, P=0.86) and OS (I 2=0%, tau^2=0.02, P=0.79) data. One study evaluated 2 different ASP-containing regimens vs hyper-CVAD. Two separate meta-analyses were executed: 1 pooling results from both treatment arms (base case) and 1 considering them separately (scenario 1). A further analysis was limited to just 2 studies, where the proportionality assumption for the HR was robust and the results consequently most statistically reliable (scenario 2). Compared with the base case, both scenarios yielded similar estimates of treatment effect but with greater heterogeneity and wider PIs. This analysis has limitations: the type of ASP-containing regimen varied (1 study assessed L-ASP regimens, 2 assessed pegaspargase, and 1 did not specify), the studies each took place in different countries potentially contributing to heterogeneity in cultural, genetic, and healthcare practices, and not all details of pts' clinical characteristics were reported to inform on comparability of the pt populations. Further, without head-to-head studies, there was no way to address whether treatment cost or institutional bias affected the results. Conclusion(s): Meta-analysis suggests that ASP-containing regimens are associated with improved rates of CR and OS in AYA (median age range 13-43 yrs) and adult (median age range 16-60 yrs) pts.

Short-Term Efficacy and Safety of Blinatumomab in Early Postinduction Intensification Therapy for Pediatric B-Cell Acute Lymphoblastic Leukemia

Background: Multidrug chemotherapy is the main treatment for children with B-cell acute lymphoblastic leukemia (B-ALL), which has been associated with multiple long-term complications and high rates of treatment non-completion due to toxicities. Recently, blinatumomab has proven to be effective and well-tolerated in the treatment of relapsed or refractory pediatric B-ALL. However, there is still a lack of reports about the real-world application of blinatumomab in pediatric B-ALL who achieved first complete remission (CR). O bjectives: To assess the short-term efficacy and safety of blinatumomab in early postinduction intensification therapy for children with B-ALL who had achieved first complete remission in a real-world setting. M ethods: A single-center retrospective analysis was performed to collect data on pediatric B-ALL patients (pts) who received blinatumomab monotherapy during early postinduction intensification therapy. All pts had undergone China Children's Leukemia Group (CCLG)-2018 induction chemotherapy until achieving CR. Blinatumomab treatment was initiated after obtaining consent from patients and caregivers, following detailed counseling about the potential risks and benefits. Efficacy was assessed based on minimal residual disease (MRD) negativity (&amp;lt;0.01%) using multiparameter flow cytometry (MFC). Adverse events (AEs) were assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. R esult: From September 2022 to July 2023, A total of 11 pts were included in this study due to chemotherapy intolerance: median age was 3 years (range, 1 to 11 years) with 54.5% (n=6) being male. Before blinatumomab therapy, MRD was detected in four pts with values of 0.024%, 0.037%, 10%, and 0.09%, respectively.The remaining pts tested negative for MRD. After one cycle of blinatumomab therapy, all MRDpos pts showed a decline in MRD, and 75% achieved undetectable MRD. The median follow-up time was 3 months. A total of 28 AEs were reported, with 75% classified as grade 1-2 and the remaining 25% as grade 3-4. The most frequently reported AEs were grade 1-2 fever (90.9%), observed within 7 days of treatment. Grade 3-4 hematological AEs included decreased white blood cell count and decreased neutrophil count. Additionally, four cases of infection, two cases of transient rash and one case of grade 2 diarrhea were observed. No pts experienced immune effector cell-associated neurotoxicity syndrome (ICANS), grade 3-4 cytokine release syndrome (CRS) or unexpected serious adverse events (SAEs). Furthermore, none of the AEs resulted in treatment delay, dose reduction or discontinuation. All pts experiencing treatment-associated toxicities recovered and proceeded to consolidation therapy. C onclusion: The use of blinatumomab in early intensification demonstrated promising short-term efficacy and a manageable safety profile in pediatric B-ALL pts. However, further confirmation of these results requires larger, randomized clinical trials.

Extensive CXCR4-MAPK Signaling Activation in the Novel B Cell Acute Lymphoblastic Subtype of CDX2/Ubtf

Background B-cell acute lymphoblastic leukemia (B-ALL) is a genetically heterogeneous group of acute leukemia with novel subtypes emerging. Since we first reported a novel subgroup B-ALL with half cases possessing CXCR4 truncated mutations and abnormal expression of CDX2 in all cases, the genomic features were further elucidated by different research groups that concurrent focal deletions lead to both upstream enhancer hijacking by CDX2 and UBTF::ATXN7L3 fusion transcript. But the molecular characterization and underlying mechanism beyond the novel subtype B-ALL remain ambiguous. Methods In order to comprehensively elucidate the molecular features, we adopt whole genome sequencing to reveal the genomic abnormalities, including snv, indel, copy number variant, and structural variation. Then, the signaling transduction and functional effect of differentially expressed genes were conducted by transcriptome analysis. Furthermore, we constructed a weighted gene co-expression network (WGCNA) and transcriptional regulons network to unravel the hub genes or transcriptional factors in the subtype. Results We retrospectively identify 2.4% (n=12) cases belonging to a novel subtype among 503 B-ALL cases with available transcriptome data by unsupervised clustering, and this subtype is characterized by CXCR4 truncated mutations or high expression of FLNA which could enhance CXCR4 signaling. Among these patients, only one male was affected showing a strong sex tendency towards females. Uniformly, all cases harbor both focal deletions encompassing between PAN3 and FLT3 located upstream of CDX2, and between UBTF and ATXN7L3, unraveled by whole genome sequencing (n=10). The focal deletions lead to overexpression of CDX2 by enhancer hijacking of upstream PAN3 and fusion transcript UBTF::ATXN7L3, respectively. In addition, 80% (n=8) cases also occurred with 1q+ which is regarded as a factor contributing to poor prognosis in leukemia and lymphoma. Transcriptomic analysis of the differentially expressed genes (DEGs) for this subtype confirmed the critical role of oncogenic MAPK signaling. Enhanced MAPK signaling was further supported by the function of the hub genes including KIAA1549 and KIAA1549L, which belong to oncogenic MAPK signaling, derived from WGCNA analysis. According to the functional enrichment analysis of DEGs, axon guidance was the only significant enriched KEGG pathway. The hub genes NTN3 from WGCNA analysis and regulon CDX2 both confirmed the functional involvement of axon guidance in this subtype. Furthermore, we prospectively identify 8 more cases by RT-PCR screening of the UBTF::ATXN7L3 transcript. Totally, twenty patients have been found in our cohort, and interestingly, there exist two cases among this subtype accumulated with multiple subclones characterized by different CXCR4 mutations, which strengthen the genotoxic stress over CXCR4 signaling. Discussion Although genomic characterization of this novel subtype has been revealed by our and others' research. The functional effect and underlying mechanism have never been elucidated. Here, we emphasize that enhanced CXCR4 signaling in this subtype may act as an upstream driver event, and it could be supplied as a therapeutic target.

A Window Study of Acalabrutinib & Rituximab, Followed By Chemotherapy & Autograft (ASCT) in Fit Patients with Treatment Naïve Mantle Cell Lymphoma (MCL): First Report of the Investigator-Initiated Australasian Leukaemia & Lymphoma Group NHL33 ‘Wamm’ Trial

Introduction Bruton's tyrosine kinase inhibitors (BTKi) have improved 1 st line therapy efficacy in elderly (Wang NEJM 2022) and young, fit, MCL-the latter with intermittent dosing during RCHOP in an alternating RCHOP/cytarabine-based regimen (Dreyling Blood 2022). However direct combination of BTKi &amp; intensive chemo is toxic in DLBCL studies. (Kuruvilla Haematol Oncol 2017). The highly selective BTKi, acalabrutinib (A), has proven efficacy and tolerability in relapsed MCL (Wang Lancet 2018). RDHAOx chemotherapy (rituximab, dexamethasone, cytarabine, oxaliplatin) prior to ASCT provides a complete response (CR) rate of 77% and favourable toxicity compared to many induction regimens (Le Gouill Blood 2017). Furthermore, Obinutuzumab-DHAP yields undetectable minimum residual disease (MRD) in 85% of young MCL patients. (Le Gouill Haematol Oncol 2019). Here we report the primary endpoint from the Australasian Leukaemia &amp; Lymphoma Group phase 2 ‘WAMM’ trial exploring a ‘sandwich’ model of an acalabrutinib-rituximab (AR) ‘window’ before RDHAOx +/- ASCT, followed by fixed-duration AR-maintenance to improve therapy response and minimise additional toxicity. Methods NHL33'WAMM' (ACTRN12619000990123) is a multicentre single-arm phase 2 trial. Key eligibility included: age 18-70 years, untreated histologically-proven stage II-IV MCL, ECOG&amp;lt;2; no contraindications to ASCT or BTKi. Pts received 2 cycles of AR (AR window); ‘A’ dose; 100mg BD PO, ‘R’ dose; 375mg/m 2 IV (day 1) every 4 weeks, followed by RDHAOx x4 cycles. Those with an objective response (CR or partial response-PR) underwent BEAM ASCT (carmustine, etoposide, cytarabine, melphalan) then AR maintenance (A; 1yr continuous &amp; R; 3-monthly x 8 cycles). Those who did not undergo BEAM ASCT were able to remain on study and proceed to maintenance AR in the event of ongoing response. Co-primary endpoints (EP) were safety; defined by lack of prohibitive toxicity causing treatment cessation AND PET-determined complete response (CR) rate after AR+RDHAOx. Secondary EP include overall response rates (ORR), toxicity, overall survival (OS) &amp; progression-free survival (PFS), MRD negativity rates and quality of life. Only Grade 3+ toxicity related to acalabrutinib was collected during the ASCT period. Baseline whole exome sequencing was performed to identify mutations, MRD analysis was done by LymphoTrack® Dx and MRD Assay platform (Invivoscribe, Inc) using Illumina® MiSeq. This study was the first Australian blood cancer trial to use telehealth and a ‘hub-and-spoke’ transplant model. Results 44 pts were enrolled from Sept 2020 to Apr 2022 (43 evaluable for the primary endpoint). Baseline characteristics were typical of a young MCL cohort: median age 59 years (Interquartile range 54-64), 77% were male, ECOG was 0-1 in 98%, 84% had stage IV, lactate dehydrogenase was elevated in 35%, Ki-67 &amp;gt;30% in 66% and blastoid/pleomorphic histology 9%. TP53 by NGS will be reported at presentation. CR rate post AR+RDHAOx induction was 88%; (95%CI 72-95) with ORR 95% and no prohibitive toxicity. AR window ORR was 93% (CR 57%). MRD negativity was achieved in 18% (7/38) post AR window, and 94% (34/36) post RDHAOx. 43 patients remained evaluable for response after R-DHAOX and pre-maintenance with 35 (80%) who underwent ASCT and 38 (86%) who commenced AR maintenance; 7 remain on maintenance. Response in specific subgroups will be reported at the meeting. At data lock, 35 pts (81%) experienced ≥1 G3+ adverse events during induction or maintenance phases, most common were neutropenia (58% of pts), febrile neutropenia (27%), thrombocytopenia (25%), diarrhea (14%). No G5 treatment-related events have occurred to date. There have been 22 SAEs, most common were COVID (3), febrile neutropenia (2) and fever (2). 5 deaths have been reported: 4 in pts with progressive disease and 1 COVID pneumonitis during AR maintenance. After a median follow up of 22 months (range 17-28m), the 2-year OS was 89%. Analysis of survival, quality of life and biomarkers will be reported with more mature follow up. Conclusion AR delivered in a sandwich approach is active and safe. An AR window yields a high ORR and compared to historical studies, improves post-chemo induction CR rates and MRD negativity. A telehealth model allowed rapid recruitment in a rare cancer.

Evaluation of Easym, a Clonotypic Mass Spectrometry Assay, and Euroflow Minimal Residual Disease Assessment in Multiple Myeloma

Introduction: Minimal residual disease (MRD) negativity is increasingly recognised as the optimal measure of therapeutic response for multiple myeloma (MM) patients and is associated with improved survival. Bone marrow (BM) assessment of MRD with next-generation sequencing (NGS) or next-generation flow cytometry (NGF) can achieve a minimum sensitivity of 10 -5 however an invasive procedure is required. Additionally, this single-site BM biopsy may be limited by specimen quality and failure to capture the spatial heterogeneity of MM. Peripheral blood-based mass spectrometry (PB-based MS) offers the potential for highly sensitive, non-invasive sequential MRD assessment. EasyM is a PB clonotypic MS assay involving de novo amino acid sequencing of the full-length M-protein and quantification of unique peptides with parallel reaction monitoring. EasyM has been compared to 8-colour multiparameter flow cytometry with a sensitivity of 10 -4 (Liyasova et al, Clin Cancer Res, 2021) and clonoSEQ (Slade et al, Blood, 2022), but not to NGF to our knowledge. In this context, we have evaluated EasyM in MM patients undergoing sequential NGF (EuroFlow platform) MRD assessment. Methods: We retrospectively identified MM patients enrolled in the Australasian Leukaemia and Lymphoma Group MM19 (ACTRN12616000772448) and MM21 (ACTRN12618001490268) trials with measurable M-protein ≥2g/L by serum protein electrophoresis and/or free light chains ≥100mg/L at baseline. Briefly, the MM19 trial evaluated the addition of ixazomib to thalidomide and dexamethasone consolidation therapy for 12 months in transplant eligible newly diagnosed MM (TE NDMM) patients undergoing front-line autologous stem cell transplantation (ASCT), whilst the MM21 trial evaluated an intensive salvage approach using daratumumab-lenalidomide-dexamethasone (DRd) as re-induction (DRd x 4 cycles) and post-ASCT consolidation (DRd x 12 cycles followed by R maintenance until disease progression) in TE NDMM patients failing (&amp;lt;partial response as best response) front-line bortezomib-based induction therapy. NGF MRD status was determined using the standardised 8-colour EuroFlow platform at pre-ASCT, post-ASCT, and end of consolidation timepoints in MM19 and MM21 patients and additionally post-cycle 2 of consolidation in MM21 patients. Matched serum samples were evaluated with the EasyM assay. Concordance between NGF and MS was assessed by the Chi-squared and McNemar's tests. Results: A total of 43 patients were identified for analysis, with 9 MM19 and 34 MM 21 patients. 1 patient was not sequenced due to low baseline values and 2 patients had no clonotypic target tryptic peptides to monitor MRD. EasyM was undetectable (MS-) in 3 (8%) patients. 2 patients achieved MS- pre-ASCT and the third achieved MS- post-cycle 2 of consolidation. All 3 patients remain in complete response (CR) at 44-48 months post-ASCT. Sequential MS (Figure 1) revealed rising EasyM levels in 2 patients, preceding relapse by 15 and 25 months; of note, 1 patient had matched BM and was NGF MRD negative. Serum samples for MS with matched BM for NGF (Table 1) were available for 25 patients pre-ASCT, 32 post-ASCT, 26 post-cycle 2 of consolidation, and 28 end of consolidation with NGF MRD negativity (NGF-) of 8%, 31%, 38%, and 75% at these timepoints, respectively. Of the 111 matched samples in total, 43 (39%) were NGF- but only 7 (6%) were MS-, and 73 (66%) were concordant. The Chi-squared test for association between MS and NGF was not significant at all 4 timepoints. The McNemar's test p-values were &amp;gt;0.999, 0.004, 0.008, and &amp;lt;0.001 for the 4 timepoints, indicating that MS+/NGF- were more likely than MS-/NGF+ discordances at all timepoints except for pre-ASCT. Of the 30 matched samples with confirmed CR status, 5 (17%) were MS+/NGF+, 19 (63%) were MS+/NGF-, and 6 (20%) were MS-/NGF- (Chi-squared and McNemar's p-values of 0.549 and &amp;lt;0.001). Conclusion: This preliminary data highlights the potential of EasyM for sequential PB-based clonotypic MS MRD monitoring in MM. Concordance with standard BM NGF was poor, with 63% of samples with confirmed CR showing detectable M-protein by EasyM but NGF MRD negativity, consistent with the higher sensitivity of EasyM. Comparison of larger sample sets and validation through prospective clinical trials is warranted to better assess the clinical utility of EasyM and rationalise BM-based assessment for MM patients.

Australasian Leukaemia & Lymphoma Group NHL35-Pacific: An Open Label Phase II Study of Pembrolizumab and Chemo-Immunotherapy As First-Line Therapy for Primary Mediastinal B-Cell Lymphoma - Trial in Progress

Background: Primary Mediastinal B-cell Lymphoma (PMBL) comprises 10% of Diffuse large B-cell lymphoma (DLBCL), primarily affecting young adults. Combination chemoimmunotherapy with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone (R-CHOP) is effective, however up to 10-20% of patients may have either refractory disease or experience relapse within 12 months of completing treatment. Consolidative radiotherapy has often been used following R-CHOP, with retrospective data suggesting a survival benefit compared with R-CHOP alone. However, mediastinal radiotherapy increases risk of breast cancer and cardiovascular disease and the recently reported randomised IELSG37 study demonstrated no improvement in progression free survival (PFS) with the use of consolidative radiotherapy following chemoimmunotherapy. Dose-adjusted Etoposide, Prednisolone, Vincristine, Cyclophosphamide, Doxorubicin and Rituximab (DA-EPOCH-R) without radiotherapy has demonstrated excellent activity in a small phase II study but with increased chemotherapy toxicity. In IELSG37, PFS was inferior for patients treated with R-CHOP-21 compared with other chemoimmunotherapy regimens, supporting intensification of therapy beyond R-CHOP-21 in this entity. The outcome for patients with relapsed/refractory PMBL is poor, with response rates of around 25% to second line therapy, and a 2-year overall survival of 15%. Therefore, there remains a need to improve initial therapy for patients with PMBL. Programmed-Death-1 (PD-1) ligands PD-L1/PD-L2 are commonly upregulated in PMBL. The PD-1 inhibitor Pembrolizumab blocks the interaction of PD-1 and PD-L1/2, and subsequent signalling, and has encouraging activity in relapsed/refractory PMBL, with an overall response rate of 43% (complete response 23%) and modest toxicity in a phase II study. ‘Window’ induction treatment involving delivery of checkpoint inhibitor therapy to patients with lymphoma, prior to initiation of chemotherapy has been investigated in phase II studies, showing encouraging efficacy and no safety concerns with this ‘chemotherapy-free’ initial treatment approach. The combination of Pembrolizumab and Rituximab is predicted to be synergistic, and in non-randomised trials in other B-cell lymphoma histologies, has demonstrated superior response rates to those expected with Rituximab monotherapy, suggesting synergism of the combination. There is therefore compelling rationale for combining R-CHOP and Pembrolizumab as first-line therapy for PMBL. This study investigates the efficacy and safety of this novel, time-limited, radiotherapy sparing regimen. Methods ALLG-PACIFIC (ANZCTR- ACTRN12621001529831) is a phase II, single arm, open-label study of R-CHOP in combination with Pembrolizumab. The trial is open to recruitment across Australia. Approximately 35 patients with newly diagnosed PMBL, will be enrolled to receive two cycles of Rituximab (375mg/m 2) plus Pembrolizumab (200mg) once every 21 days ('window phase') followed by six cycles of R-CHOP plus Pembrolizumab once every 21 days ('induction phase') followed by five cycles of Pembrolizumab 400mg once every 42 days ('consolidation phase') (Figure 1). Adults (≥18 years) with treatment naïve histologically confirmed PMBL and adequate organ function are eligible. Key exclusion criteria are the presence of active autoimmune disease, requiring recent immunosuppressive therapy, life-threatening or organ-compromising lymphoma symptoms requiring urgent cytoreductive therapy, and other medically significant conditions that preclude eligibility to receive R-CHOP. Patients who require urgent cytoreductive therapy following initiation of window phase treatment may proceed immediately to induction phase chemotherapy. The primary endpoint is 18-month event free survival. Key secondary endpoints include response to window phase treatment, overall survival, requirement for radiotherapy and safety of treatment including rates of early discontinuation due to treatment toxicity. Several biomarkers are also being investigated for their predictive value for treatment response including minimal residual disease status (measured by Adaptive Immunoseq and CAPP-Seq), PET-CT parameters (e.g., Metabolic tumour volume), and PD-1/PD-L1 expression and 9q24 alterations.

Tyrosine Kinase Inhibitor (TKI) Discontinuation in Non-Allografted Ph+ Acute Lymphoblastic Leukemia Patients, a Campus ALL Real-Life Study

Introduction. Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) patients are commonly treated with tyrosine kinase inhibitors (TKI) in combination with either steroids, chemotherapy and more recently also immunotherapy. In the past, allogeneic transplant (SCT) was considered the only curative option; however, with the introduction of more potent TKIs as well as immunotherapy this milestone is nowadays debated, mostly for patients who achieve a molecular response. Moreover, as in chronic myeloid leukemia (CML), it is becoming relevant to understand if patients may over time discontinue TKI treatment. For this purpose, it is pivotal to report the outcome of Ph+ ALL patients who, for any reason, stopped TKI treatment. Patients and Methods. Forty-seven adult Ph+ ALL patients treated since 1 January 2000, and who did not undergo a SCT, were retrospectively collected from 12 Italian centers participating to the Campus ALL network. Their treatment plan included a TKI +/- chemotherapy according to the center current practice and/or according to the ongoing national trial they were enrolled in. The median age was 63 years (20-84), 20 patients (43%) were males, 30 patients harbored a p190 transcript, 15 a p210 transcript and 2 had both transcripts. Twenty-six patients were treated within a trial, while 21 were off-protocol. For 32 patients, induction was based only on a TKI plus steroids, whereas the remaining 15 received a combination of a TKI plus chemotherapy (in 3 cases high intensity protocols such as the NILG (Northern Italian Leukemia Group) and HCVAD regimens, in 12 low dose chemotherapy). The reasons not to transplant patients were: donor unavailability (5), clinical decision, mainly due to age/unfitness (30), patient's refusal (4), and achievement of a molecular response (i.e. at least BCR-ABL/ABL ≤0.01%) (8). The median follow-up was 60 months, with a median overall survival (OS) not reached at the last follow-up and a median disease-free survival (DFS) of 12 years. At the last follow-up, 12/47 patients had experienced a relapse. At the end of the induction (i.e. after 3 months, at a median of +82 days, from treatment initiation), 27 patients had achieved a molecular response. Overall. a molecular response was obtained in 40/46 pts (data not available for 1 case) after a median of 5 month, and was associated with a significantly lower hazard of disease recurrence (HR=0.057, 95% CI: 0.006-0.51, p=0.011) after adjusting for gender, fusion protein, association with chemotherapy, CMR at 3 months. Results. TKI treatment was discontinued in 14 of the 47 patients evaluated. The reasons for discontinuation were either toxicity (6) or clinical/patient decision (8). Eight patients harbored a p190 transcript, 5 a p210 transcript and 1 carried both. At the time of discontinuation, the median age was 75 years (23-87) and patients had been on a TKI for a median of 57.5 months (8-160) prior to stopping treatment. For these cases, the median WBC at diagnosis were 8.6 x 10 9/l (2.1-306 x 10 9/l). In 7 patients the first TKI used was imatinib, in 3 dasatinib, in 3 ponatinib and in 1 nilotinib. All patients but 1 had achieved a molecular response before stopping treatment; the only patient who never achieved a molecular response prior to discontinuing the TKI had a rapid relapse (1 month). At the last follow-up, 9 cases were still in treatment-free remission (TFR), whereas 5 eventually relapsed after 1, 1, 4, 14 and 30 months, respectively. Re-challenge with a TKI led to a hematological and molecular response in 3 of the 5 patients. The remaining 2 patients, who had been previously heavily treated and whose TFR was of only 1 month, received salvage standard chemotherapy but eventually died from ALL progression. The median time of TFR for the entire cohort of 14 patients was 20.5 months (1-82). When considering only the 9 patients who remain off treatment, the median time of TFR was 29.5 months (7-82) (Table 1, Figure 1). Conclusions. We report the outcome of 14 Ph+ ALL patients who discontinued TKI treatment due to various reasons. Nine of them are still on TFR after more than 2 years at the last follow-up, reinforcing the concept that a TFR is feasible in selected adult Ph+ ALL patients. Of further relevance, TKI re-challenge was successful in 3/5 patients who relapsed, similarly to what observed in CML.

Higher Prevalence of Chronic Kidney Disease in Myelodysplastic Syndromes Patients Compared to Age- Adjusted General Population - Results from the Polish Adult Leukemia Group (PALG) Registry

Introduction Chronic comorbidities that are common in the elderly population can have a significant impact on the clinical course, the choice of treatment, and survival of myelodysplastic syndromes (MDS) patients. No studies have focused on the coexistence of two diseases that are common in the elderly population, chronic kidney disease (CKD) and MDS, so the epidemiological data and clinical implications of both diseases occurring together are unknown. Aims Primary objective: to assess the prevalence of CKD in patients with MDS in comparison to the age-adjusted general population. Secondary objective: to evaluate the impact of CKD on clinical course in MDS patients. Methods This was a prospective analysis using clinical and laboratory data from MDS patients who were registered in the Polish Adult Leukemia Group (PALG) Registry from 2010 to 2023. Data have been provided by 28 hematologic centers. CKD was defined as an eGFR &amp;lt; 60 mL/min/1.73m², disregarding albuminuria since urinalysis results were not recorded in the database. The stages of CKD were classified based on eGFR according to the NKF KDOQI National Kidney Foundation Kidney Disease Outcome Quality Initiative guidelines, and eGFR was calculated using CKD-EPI equation. For comparison of the prevalence of CKD in MDS subjects aged ≥60 years to the general population, we used data from the PolSenior 2 study (covering the years 2018-2019). Data were age and sex standardized using demographic tables from Statistics Poland (https:// demografia.stat.gov.pl/bazademografia/Tables.aspx). Median survival time was calculated using Kaplan-Meier estimator. Multivariate analysis was performed using Cox regression. Results Overall, data (including eGFR) were available for 1813 MDS patients. Median age at diagnosis was 71 years [IQR 64 - 78]. and 55.3% patients were male. Sixty percent of the patients were diagnosed as IPPS lower risk. At the time of MDS diagnosis, CKD was detected in 479 patients (26.4%). Among patients aged ≥ 60, the crude rate of CKD was 30.3%. The standardized rate of CKD in the general population aged ≥ 60 years was significantly lower than in the similarly aged MDS group, with rates of 13.2% [CI 12.3-14.1] and 25.5% [CI 22.9-28.4]; p&amp;lt;0.001, respectively. (Figure 1) Patients with CKD were significantly older (median 78 yo) than those without CKD (median 68 yo; p&amp;lt;0.001), and more likely to have diabetes (33.2% vs 19.7%; p&amp;lt;0.001), and to have coincidence of another malignancy (21.6%) than those without CKD (14.9%; p=0.001). Median hemoglobin concentration was significantly lower in the CKD group (8.9 g/dL) than in the non-CKD group (9.4 g/dL; p &amp;lt; 0.05). Subjects with decreased eGFR were more likely to be dependent on RBC transfusion (56.5%) than subjects with eGFR ≥ 60 ml/min per 1.73m 2 (48.9%; p=0.0008). Median survival of patients with eGFR ≥ 60 ml/min per 1.73m 2 was 2.5 y [CI 1.0-6.1] vs 1.4 y [CI 0.6-4.2] for CKD. In multivariate analysis we found that CKD stage, age ≥ 65, higher IPSS score, high-risk IPSS cytogenetics and ECOG &amp;gt;1 were independent predictors of shorter survival. (Figure 2). Conclusions Myelodysplastic syndrome (MDS) subjects are more likely to have chronic kidney disease (CKD) than the general population. The presence of CKD in MDS patients is associated with worse overall survival and higher RBC transfusion requirement.