Ph-negative B-ALL Research Articles

Total body irradiation versus thiotepa/busulfan-based conditioning regimens for myeloablative allogeneic stem cell transplantation in adults with acute lymphoblastic leukemia.

Total body irradiation (TBI)-based conditioning regimens are generally recommended for allogeneic HSCT (allo-HSCT) in patients with acute lymphoblastic leukemia (ALL). Recent evidence suggests that modern chemotherapy-based regimens may be as effective. This multicenter retrospective study compared the clinical outcomes of myeloablative allo-HSCT with thiotepa, busulfan, and cyclophosphamide/fludarabine (TTB) to TBI-based conditioning. Between 2002 to 2018, 63 and 114 patients received TTB- and TBI-based conditioning regimens, respectively. The 5-year cumulative incidence of relapse was lower in the TBI cohort compared to the TTB cohort (30% [95% CI, 22-38] versus 47% [95% CI, 36-59]; P = 0.03). Multivariate analysis identified T-ALL, Ph-negative B-ALL, and measurable residual disease associated with a higher relapse risk. The 5-year cumulative incidence of non-relapsed mortality (NRM) was significantly lower with TTB (12% [95% CI, 5-20]) compared to TBI (25% [95% CI, 18-33]) (P = 0.001). Multivariate analysis found TBI conditioning, older age, and advanced stages of ALL at transplantation associated with a higher NRM. No statistical difference was seen in overall survival (49% [95% CI, 40-58] and 46% [95% CI, 35-60]) in the TBI and TTB groups, respectively; P = 0.9). The study suggests that TTB-based conditioning may be a promising option for ALL patients undergoing allo-HSCT, as it resulted in similar OS and lower NRM than TBI-based conditioning.

Abstract 541: Establishment of Inotuzumab ozogamicin resistant leukemia cell lines; Focusing on p-gp and DNA damage repair for overcoming drug resistance

Abstract Introduction: Inotuzumab Ozogamicin (IO) is a humanized anti-CD22 monoclonal antibody conjugated with chalicheamicin, which causes single- and double-strand DNA breaks. Although IO shows a high CR/CRi rate in relapsed/refractory CD22-positive B-cell acute lymphoblastic leukemia (ALL), the duration of remission is short due to early acquisition of resistance. Therefore, the present study attempted to enhance the cytotoxicity of IO by focusing on polyadenosine diphosphate-ribose polymerase (PARP) inhibition. Furthermore, IO-resistant cell lines were newly established to investigate the mechanism of IO resistance. Methods: Reh cell line derived from Ph-negative B-ALL cells was used. To establish IO-resistant cell lines, Reh cells were long-term exposed to IO, followed by limiting dilution. FACS analysis evaluated the CD22 positivity and the induction of apoptosis. WTS assay determined the cell growth inhibition effects. The Comet assay quantitatively assessed DNA damage. Gene expression profiles were determined by using DNA microarray. Results: The 50%-inhibitory concentration (IC50) of IO was 2.1 ng/mL in Reh cells. Reh cells were synergistically sensitized to IO by the addition of non-toxic concentrations of PARP inhibitors, olaparib or talazoparib, with the Combination Index of 0.19 and 0.42, respectively. Moreover, these combinations augmented the induction of apoptosis (23.5% in IO alone, 51.7% in IO + olaparib, 66.1% in IO + talazoparib). The Comet assay demonstrated that DNA strand breaks observed 1h after IO administration were repaired 6h later. In the combination of IO with olaparib or talazoparib, DNA damage remained even at 6h, suggesting the inhibition of DNA repair by PARP inhibitors. Next, six IO-resistant cell lines were established with IC50 more than 60-fold that of parental cells. All these cell lines kept CD22 expression. These cell lines were also resistant to apoptosis induced by IO. In addition of olaparib or talazoparib to IO, the IC50 of IO decreased by 40% to 70% in 6 IO-resistant cells. These combinations also augmented the induction of apoptosis (24.2% in IO alone, 45.3% in IO+olaparib, and 56.8% in IO+talazoparib). DNA microarray was performed to compare gene expression profiles between parental and IO-resistant cell lines. ABCB1 (p-gp), a drug efflux pump that causes multi-drug resistance, was overexpressed in resistant cell lines. Moreover, the addition of p-gp inhibitor, PSC-833, to IO enhanced the cell growth inhibition and induction of apoptosis due to more DNA strand break. Conclusion: The present study demonstrated that the combination of IO with PARP inhibitors exerted synergistic cytotoxicity via the inhibition of DNA repair. In addition, it was suggested that overexpression of p-gp caused IO resistance, which was partially reversed with the combination of PARP inhibitors or a p-gp inhibitor. Citation Format: Naoko Ida, Miyuki Okura, Naoko Hosono, Takahiro Yamauchi. Establishment of Inotuzumab ozogamicin resistant leukemia cell lines; Focusing on p-gp and DNA damage repair for overcoming drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 541.

DNA Copy Number Alterations and Copy Neutral Loss of Heterozygosity in Adult Ph-Negative Acute B-Lymphoblastic Leukemia: Focus on the Genes Involved.

The landscape of chromosomal aberrations in the tumor cells of the patients with B-ALL is diverse and can influence the outcome of the disease. Molecular karyotyping at the onset of the disease using chromosomal microarray (CMA) is advisable to identify additional molecular factors associated with the prognosis of the disease. Molecular karyotyping data for 36 patients with Ph-negative B-ALL who received therapy according to the ALL-2016 protocol are presented. We analyzed copy number alterations and their prognostic significance for CDKN2A/B, DMRTA, DOCK8, TP53, SMARCA2, PAX5, XPA, FOXE1, HEMGN, USP45, RUNX1, NF1, IGF2BP1, ERG, TMPRSS2, CRLF2, FGFR3, FLNB, IKZF1, RUNX2, ARID1B, CIP2A, PIK3CA, ATM, RB1, BIRC3, MYC, IKZF3, ETV6, ZNF384, PTPRJ, CCL20, PAX3, MTCH2, TCF3, IKZF2, BTG1, BTG2, RAG1, RAG2, ELK3, SH2B3, EP300, MAP2K2, EBI3, MEF2D, MEF2C, CEBPA, and TBLXR1 genes, choosing t(4;11) and t(7;14) as reference events. Of the 36 patients, only 5 (13.8%) had a normal molecular karyotype, and 31 (86.2%) were found to have various molecular karyotype abnormalities-104 deletions, 90 duplications or amplifications, 29 cases of cnLOH and 7 biallelic/homozygous deletions. We found that 11q22-23 duplication involving the BIRC3, ATM and MLL genes was the most adverse prognostic event in the study cohort.

A Phase 1 Study of Venetoclax in Combination with a Pediatric-Inspired Regimen for the Treatment of Newly Diagnosed Adults with B-Cell Ph-like ALL

Background: Aberrant overexpression of pro-survival Bcl-2 family proteins is one mechanism by which leukemic cells circumvent apoptosis. BCL-2 overexpression is common in various subtypes of B-acute lymphocytic leukemia (ALL), including Philadelphia (Ph)-like ALL. Ph-like ALL is a chemotherapy-resistant disease associated with higher rates of induction failure and persistent measurable residual disease (MRD), and poor overall survival (OS) outcomes with frontline chemotherapy regimens, compared to other subtypes. Venetoclax (VEN) is a selective BCL2 inhibitor, and its addition to pediatric-type frontline regimens could improve response and long-term outcomes for B-ALL, including Ph-like subtype. Design: This is a phase 1 study with an expansion cohort investigating the safety of combining VEN with induction (IND) and consolidation (CON) cycles of the CALGB 10403 backbone regimen (NCT05157971). Post CONS therapy was per the treating physician discretion. The study enrolled newly diagnosed adults [18-54 years (yrs)] with Ph-negative B-ALL. To enrich the study for Ph-like ALL, we excluded patients (pts) with KMT2A-rearranged, TCF3::PBX1, and ETV6::RUNX1 subtypes at diagnosis. Identification of Ph-like ALL was performed using RNA-sequencing, conventional cytogenetics, fluorescence in situ hybridization, and whole genome array studies. Dose level (DL) 1 of VEN was 400 mg orally daily on days 1-14 of IND and CON, with a ramp-up dosing during IND [Day 1= 100 mg, Day 2= 200 mg, Days 3-14= 400 mg/day]. Results: We enrolled 14 pts as of July 1 st, 2023. The median age was 33 (20-53) yrs, of which 9 pts were males and 13 (93%) were Hispanics. Seven (50%) pts had Ph-like ALL (6 with CRLF2-alterations, 1 JAK2-fusion). Six pts were treated on the phase 1 part, and no dose limiting toxicity was observed during IND. Among 14 pts that completed IND, all achieved complete remission (CR), including 1 pt who required an extended IND phase, and 79% (n= 11) achieved MRD- (<0.01%) by multicolor flow (MCF) on day 28 of IND. Eleven pts completed CONS, and all achieved undetectable MRD CR or CR with incomplete count recovery (CRi) by MCF. Post CONS next-generation sequencing of MRD (clonoSEQ) was available for all 11 pts who completed CONS, and 7 (64%) were undetectable while 4 were detected at very low levels (range: 0.0007-0.0024%). Median time to neutrophil count ≥1000 and platelet count ≥100,000 were 19 (15-26) and 14 (2-27) days from starting IND, respectively. No pt died during IND or CONS cycles. Grade ≥3 adverse events at least possibly related to venetoclax and/or the C10403 regimen that occurred in ≥ 20% of evaluable pts during either IND or CONS cycles were leukopenia (100%), neutropenia (100%), lymphopenia (100%), anemia (70%), thrombocytopenia (50%), hyperbilirubinemia (30%) and hypertriglyceridemia (20%). Only 1 pt underwent consolidation with allogeneic stem cell transplant while in remission. With a median follow up for the entire cohort of 7.2 months (range: 1.9-16.1 months), only 1 pt with Ph-like ALL relapsed and he is currently alive. Conclusion: The addition of 14 days of VEN at 400 mg daily dose to a pediatric-inspired regimen during IND and CONS was safe in adults with newly diagnosed B-ALL and did not delay counts recovery. The addition of VEN led to a promising higher than expected MRD- CR rate in high-risk B-ALL, including for pts with Ph-like subtype. The study is actively enrolling on the expansion cohort, and BH3 profiling on pre-treatment and post relapse samples will be performed to determine BCL-2 dependency and correlates to early MRD- response.

Outcomes and Prognostic Factors of Second Allogeneic Hematopoietic Cell Transplantation in Patients with Acute Lymphoblastic Leukemia: A Study from the Adult Acute Lymphoblastic Leukemia Working Group of the Japanese Society for Transplantation and Cellular Therapy

Background Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment option frequently used in patients with acute lymphoblastic leukemia (ALL). However, relapse after allo-HCT remains the main concern because it is associated with poor outcomes, with a long-term survival rate < 10 %. There is no standard treatment for patients with ALL who relapsed after allo-HCT. Second allo-HCT (allo-HCT2) is a curative treatment option for patients with ALL who relapsed after the first allo-HCT (allo-HCT1). However, data on allo-HCT2 in patients with ALL are limited, and the indications and outcomes of allo-HCT2 are unclear. Therefore, this study aimed to investigate the outcomes and prognostic factors of patients who underwent allo-HCT2 after ALL relapse. Methods This study included 425 adult patients with ALL who underwent allo-HCT2 after relapse between January 2001 and December 2020. The primary endpoint was 2-year overall survival (OS), which was evaluated using the log-rank test. Prognostic factors for the primary endpoint were evaluated using the multivariable Cox proportional hazards model. The variables considered in the Cox proportional hazards model are listed in the Table. The impacts of the candidate factors are shown as hazard ratios (HRs) and 95% confidence intervals (CIs). Additionally, we performed an analysis stratified by disease and disease status because Philadelphia chromosome (Ph)-positive B-ALL could affect the treatment and disease status at allo-HCT2 and the outcome. Results The median age at allo-HCT2 was 36 years (interquartile range; 27-48 years) and 220 patients (52%) were male. According to the Eastern Cooperative Oncology Group, 94 patients (22%) had a performance status of > 2. There were 235 patients (55%) with Ph-negative B-ALL, 122 patients (29%) with Ph-positive B-ALL, and 68 patients (16%) with T-ALL. Regarding disease status at allo-HCT2, 217 patients (51%) had any complete response (CR). One hundred forty-eight patients (35%) received myeloablative conditioning regimen. Ninety patients (21%) received related bone marrow (BM) or peripheral blood (PB) transplantation, 137 patients (32%) received unrelated BM or PB transplantation, and 198 patients (47%) received unrelated cord blood (CB) transplantation. The median observation time of survivor after allo-HCT2 was 22.3 (interquartile range; 6.3-82.5) months and 2-year OS was 28.0% (95% CI, 23.7-32.4). After stratified disease and disease status, the 2-year OS was 56.5% (95% CI, 44.6-66.8), 31.7% (95% CI, 24.0-39.7), 21.5% (95% CI, 10.6-34.9), and 13.1% (95% CI, 8.4-18.8) in any CR (Ph-positive B-ALL), any CR (other), active disease (Ph-positive B-ALL), and active disease (other), respectively ( P < 0.001) (Figure). In multivariable analysis, Ph-positive B-ALL (HR, 0.48; 95% CI, 0.36-0.65; P < 0.001), tacrolimus-based GVHD prophylaxis at allo-HCT2 (HR, 0.72; 95% CI, 0.54-0.95; P = 0.022) were identified as significantly positive prognostic factors for 2-year OS, while allo-HCT1 to allo-HCT2 < 12 months (HR, 1.38; 95% CI, 1.02-1.88; P = 0.038), relapse within 12 months after allo-HCT1 (HR, 1.37; 95% CI, 1.01-1.85; P = 0.043), ECOG PS > 2 (HR, 1.89; 95% CI, 1.44-2.49; P < 0.001), active disease at allo-HCT2 (HR, 1.88; 95% CI, 1.46-2.42; P < 0.001), unrelated BM or PB transplantation at allo-HCT2 (HR, 1.78; 95% CI, 1.22-2.59; P = 0.003), and CB transplantation at allo-HCT2 (HR, 1.54; 95% CI, 1.09-2.18; P = 0.013) were identified as significantly negative prognostic factors for 2-year OS. Conclusion In this study, we demonstrate that the 2-year OS was 28.0% in patients with ALL who underwent allo-HCT2 and identified the prognostic factors that may guide patients to benefit from allo-HCT2.

Mini-Hyper-CVD Plus Venetoclax for Treatment of Older Adults with Newly Diagnosed Ph-Negative B-ALL or T-ALL

Introduction Treatment of Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) in older patients (pts) is challenging due to poor tolerance of conventional chemotherapy and chemo-resistant disease. Pre-clinical work demonstrates that lymphoblasts are BCL2-dependent and sensitive to the BCL2 inhibitor venetoclax (VEN). We hypothesized that VEN plus dose-reduced hyper-CVD (cyclophosphamide, vincristine, dexamethasone) chemotherapy would be well tolerated and effective in older pts. We previously reported the safety and tolerability of VEN plus hyper-CVD in newly diagnosed and relapsed/refractory (R/R) pts (Jain ASH 2019), with a maximum tolerated dose of VEN 600 mg daily on days 1-21 per 28-day cycle. Preliminarily efficacy was promising in newly diagnosed pts, which prompted study extension to phase (P) 2, enrolling newly diagnosed older pts with Ph-negative (neg) B-ALL and T-ALL. Methods Pts with Ph-neg B-ALL or T-ALL were enrolled in a multi-center Phase Ib/II study (NCT03319901). In P1, both R/R pts and newly diagnosed pts ≥ 60 years (yrs) were enrolled. In P2, only newly diagnosed pts ≥ 55 yrs old or ≥ 50 yrs old with BMI ≥ 35 kg/m2 were enrolled. Pts began with VEN ramp-up (P1 over 7d; P2 over 3d) to target dose (P1: dose level [DL]1 400 mg/d; DL2 600 mg/d; P2 400 mg/d), Figure 1. Hyper-CVD, including central nervous system (CNS) prophylaxis with intrathecal chemotherapy, was then given with VEN per DL for 21/28 days per cycle, for up to 8 cycles. Following completion of hyper-CVD courses, pts received VEN plus POMP maintenance for up to 2 yrs. Pts were recommended to receive fewer than 8 cycles of hyper-CVD in the setting of toxicity or to proceed to allogeneic hematopoietic stem cell transplant (HSCT) per physician discretion. This report updates follow-up of the newly diagnosed pts enrolled in P1 and the P2 cohort. Complete remission (CR) was defined as <5% marrow blasts, no evidence of extramedullary or CNS leukemia, ANC >1.0 K/uL and platelets >100 K/uL. Measurable residual disease (MRD) was evaluated by multicolor flow cytometry (MFC) and negative defined as <0.01%. Survival outcomes are presented via Kaplan Meier. Results In total, 30 newly diagnosed pts [P1 11 (DL1=3; DL2=8); P2 18] were treated with a median age of 68 yrs (range, 57-81 yrs, n=12 [40%] ≥70 yrs); n=15 (50%) women, n=4 (13%) Hispanic, and n=1 (3%) Black. Twenty-three (77%) pts had B-ALL and 7 (23%) pts had T-ALL (6/7 early T-cell precursor). Two (6%) pts had central nervous system (CNS) involvement at diagnosis (1-CNS3, 1-CNS2). High risk genetics were present in 56% (13/23) of B-ALL pts: TP53 (n=9 associated with complex [n=3] or hypodiploid [n=5] karyotype), KMT2A (n=1), IKZF1 abnormality (n=2), and Ph-like (n=1). Eight B-ALL pts had received prior chemotherapy for multiple myeloma (n=6; n=4 auto HSCT, n=5 lenalidomide), diffuse large B-cell lymphoma (n=1, RCHOP), and breast cancer (n=1, docetaxel, carboplatin, trastuzumab). The median number of hyper-CVD cycles received was 4 (range 1-8) among the 27 pts who have completed the hyper-CVD phase of treatment (3 pts are currently receiving consolidation). Mortality within 30 days was 3% (n=1). One patient died in CR due to sepsis during cycle 4. Venetoclax did not impair count recovery: median time from C1 to C2 was 34 days (range 27-47). Dose adjustments of VEN occurred in 4 pts (15%). An MRD-neg CR was achieved in 25/30 (83%) pts. The median cycles to achieve both CR and MRD negativity by MFC was one (range: CR 1-2 cycles; MRD negativity 1-4 cycles). Remaining pts had refractory disease (n=4, 13%), or were not assessed (n=1, 3%) due to early death. Of the 25 pts who achieved CR, 11/25 (44%) received allogeneic HSCT in CR1 after a median of 200 days (range 138 to 347). With a median follow-up of 16.4 months, the estimated 12- and 24-month OS are 82.1% (95% CI 66, 98) and 74.6% (95% CI 54, 95), Figure 2; and RFS are 82.9% (95% CI 65, 100.0) and 67.8% (95% CI 44, 92), respectively. At data cut-off, 22 pts (73%) are alive. Death events (n=8, 27%) were due to early mortality (n=1, related to both ALL and infection), post HSCT complications (n=3), refractory ALL (n=1), relapsed ALL (n=1), sepsis in CR (n=1), and complications of cardiac surgery in CR (n=1). Conclusion In this ongoing study, the addition of VEN to hyper-CVD in newly diagnosed ALL was well tolerated with encouraging responses. A future amendment will incorporate blinatumomab consolidation for pts with B-ALL.

Venetoclax+Azacytidine Followed By Modified BuCy Conditioning Regimen for High Risk or Refractory/Relapsed Acute Lymphoblastic Leukemia and High Risk Myelodysplastic Syndromes

Background:Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only potential curable treatment for myelodysplastic syndromes (MDS) and acute lymphoblastic leukemia (ALL). However, for patients with high-risk or refractory relapsed (R/R) B-ALL with allo-HSCT, the three-year overall survival (OS) rate is only 5-10%, more worse in T-ALL. It is widely known that MDS patients in the high-risk group do not benefit from induction chemotherapy, the five-year OS rate is 23-39% when they received allo-HSCT. Nevertheless, relapse remains a significant cause of treatment failure after allo-HSCT, highlighting the urgent need for improved conditioning regimens that can improve prognosis and reduce relapse rates. Azacytidine (AZA) combined with Venetoclax (VEN), showed a synergistic anti-tumor activity against several hematological malignancies, Therefore, we explored AZA+VEN (VA) combined with modified BuCy(mBuCy) (semustine, cytarabine, busulfan, and cyclophosphamide) conditioning regimen and assessed the safety and effectiveness. Aims ：The aim of this study is to assess the safety, and effectiveness of the VA treatment regimen followed by mBuCy as conditioning regimen for high-risk or R/R ALL(NCT05809167) and high-risk MDS(NCT03256071) . Methods:Patients diagnosed with high-risk or R/R ALL or high-risk MDS (IPSS-R score), undergoing VA+mBuCy as conditioning regimen, and consolidation treatment with demethylating drugs every three months after transplantation, for a total of 8-12 cycles. Results:Patients diagnosed with high-risk or R/R ALL(n=11) or high-risk MDS (IPSS-R score)(n=8) were enrolled between January 13, 2022, and June 9, 2023. The ALL cohort comprised of 5 Ph-negative B-ALL, 2 Ph-positive B-ALL, 3 mixed phenotype leukemias (MPAL), and one T-lymphoblastic lymphoma/leukemia (T-ALL/LBL). There were 7 males and 4 females, with a median age of 33 years (17-54 years) (Table 1). Out of the eleven patients, four had previously undergone Chimeric Antigen Receptor T-Cell Immunotherapy (CAR-T) therapy, and one patient had received Blinatumomab. One patient experienced relapse, another patient was refractory, and 3 patients had extramedullary infiltration. All patients achieved morphological complete remission prior to transplantation, and 10 patients (90.9%) achieved a MRD negative remission. Additionally, all the transplantations successfully completed, with a median time to absolute neutrophil counts (ANC) recovery of 12 days (11-15 days) and platelet (PLT) recovery of 16 days (15-21 days). The median follow-up time was 6.4 months (2.4 -13.6 months), no patient experienced relapse or death, the OS and DFS are both 100%. There were no grade 3 or higher adverse events (AEs), hepatic veno-occlusive disease (VOD),and the transplant-related mortality (TRM). Four patients who developed acute graft-versus-host disease (aGVHD) post-transplantation, all cases involved grade I/II skin aGVHD, and one of them involved grade III GI aGVHD, and no chronic graft-versus-host disease (cGVHD) were observed during the follow-up period. By the endpoint of follow-up, Cytomegalovirus (CMV) activation was 45.4% (5/11) and Epstein-Barr virus (EBV) activation was 27.3% (3/11). The MDS cohort consisted of 7 cases of MDS-EB-I, 1 case of MDS-EB-II. There were 5 males and 3 females, with a median age of 42 years (23-57 years)(Table 2). Two patients received chemotherapy before transplantation, and the other six patients directly received allo-HSCT. In MDS cohort, the median recovery time for ANC was 12 days (11-13 days) and PLT was 17.5 days (16-20 days). The median follow-up was 14.3 months (1.2-18.3 months), no patient had relapsed or died, both OS and DFS are 100%. There were no grade 3 or higher AEs, and TRM. One patient developed VOD. Three patients developed aGVHD after transplantation, all involving degree I/II skin aGVHD, and there was one case of cGVHD during the follow-up period, where the patient developed a mild pulmonary cGVHD. By the endpoint of the follow-up, the rate of CMV activation was 37.5% (3/8) and EBV activation was 25% (2/8). Conclusion:The VA combined with the mBuCy proves to be a effective and safe conditioning regimen for high-risk ALL and MDS patients. However, more patients are needed for follow-up and validation.

ALL-545 Is the Distribution of Gene Copy Number Alteration in Ph-Positive B-ALL Different From Ph-Negative B-ALL?

ALL-545 Is the Distribution of Gene Copy Number Alteration in Ph-Positive B-ALL Different From Ph-Negative B-ALL?

Positioning blinatumomab in the frontline of adult B-cell acute lymphoblastic leukemia treatment.

Blinatumomab is a bispecific T cell engager that has shown efficacy in relapsed/refractory Philadelphia chromosome (Ph)-positive and Ph-negative acute lymphoblastic leukemia (ALL). Considering its favorable safety and activity in advanced ALL, blinatumomab as a targeted immunotherapy is fast gaining a frontline position in the ALL treatment paradigm. There have been multiple completed and ongoing studies showing significant promise with improved response rates and survival outcomes and decreased treatment toxicity and need for multi-agent chemotherapy regimens. The early use of blinatumomab has established success in Ph-negative and Ph-positive B-ALL, and this has extended to older adults with ALL who have historically had substantially inferior outcomes compared to their pediatric and young adult counterparts. Herein we will review the current data describing the early use of blinatumomab in newly diagnosed adults with B-cell ALL and future directions.

Mini-hyper-CVD plus inotuzumab ozogamicin (InO), with or without blinatumomab (Blina), in older patients with newly diagnosed Philadelphia chromosome (Ph)-negative B-cell acute lymphoblastic leukemia (ALL): Updates from a phase II trial.

e19025 Background: The overall survival (OS) of patients (pts) with relapsed/refractory B-ALL has improved with the introduction of InO and Blina. Compared to conventional chemotherapy, the incorporation of these agents into the frontline setting of older pts with ALL may allow the use of less chemotherapy and potentially improve outcomes. Methods: Adults ≥60 yrs with newly diagnosed Ph-negative B-ALL received mini-Hyper-CVD (mini-HCVD) for up to 8 cycles. Initially, InO was given at 1.3-1.8mg/m2 on Day (D) 3 of Cycle (C) 1 and 0.8-1.3mg/m2 on D3 of C2-4. Rituximab (if CD20+) and prophylactic IT chemotherapy were given for the first 4 cycles. Responders received POMP maintenance for up to 3 yrs. Beginning with pt #50, InO was given in fractionated doses each cycle (0.6 mg/m2 on D2 and 0.3 mg/m2 on D8 of C1; 0.3 mg/m2 on D2 and 8 of C2-4) and 4 cycles of Blina were given following 4 cycles of mini-HCVD plus InO. Maintenance was with 12 cycles of POMP and 4 cycles of Blina (1 cycle of Blina after 3 cycles of POMP). Results: 83 pts were treated, of whom 6 were in complete remission (CR) at enrollment(Table 1). Among 77 evaluable pts, 76 (99%) responded (CR, 90%). Among responders, the rates of MRD negativity by flow cytometry were 79% and 94% after C1 and overall, respectively. No early death was observed. Among 82 pts in remission, 11 (13%) relapsed, 4 (5%) underwent ASCT, 34 (41%) remain in ongoing continuous remission, 33 (41%) died in remission, of whom 9 died after developing MDS/AML. Three pts (4%) developed veno-occlusive disease, 2 after subsequent ASCT. After a median follow-up of 65 months (range, 6-126), the 5-yr continuous remission duration and OS rates were 78% and 48%, respectively. Age ≥70 and adverse cytogenetics were associated with worse outcomes. The inferior outcome in pts ≥70 yrs was primarily attributed to higher rates of death in CR. The 5-yr OS for pts age 60-69 yrs without adverse cytogenetics (n=40), age 60-69 with adverse cytogenetics (n=15), age ≥70 without adverse cytogenetics (n=24) and age ≥70 with adverse cytogenetics (n=4) were 72%, 27%, 38% and 0%, respectively. Conclusions: Favorable outcomes were observed in older pts with newly diagnosed Ph-negative ALL treated with mini-HCVD plus InO, with or without Blina. The 5-yr OS was 48%. Clinical trial information: NCT01371630 . [Table: see text]

Abstract 5517: Pegaspargase is a viable option in elderly adults with acute lymphoblastic leukemia

Abstract Pegaspargase (peg-asp) is a pegylated form of asparaginase with a longer half-life used in pediatric-inspired chemotherapy for treatment of adult acute lymphocytic leukemia (ALL). Peg-asp appears to confer a survival advantage, but use in older adults is limited by concern for toxicity, though incidence and associated factors are poorly characterized. Our primary objective was to compare peg-asp tolerability in different age groups; secondary objectives were assessment of patient- (pt) and disease-dependent factors associated with toxicity. We retrospectively reviewed 58 ALL pts treated with at least 1 dose of peg-asp (500-2500IU/m2) at our institution between 2016-2021. We used χ-squared- and Fisher’s test, and multivariable regression analysis to assess relationships between pt-factors and toxicities. Median doses received was 2 (range 1-7). 38 pts were 40 years or older, 20 were >60 years. 18 received PEG during induction only, 8 in consolidation only, 27 in both, and 5 during salvage therapy post-relapse. 17 had Philadelphia (Ph) positive B-ALL; 32 Ph negative B-ALL; 7 T-ALL; and 2 had mixed phenotype acute leukemia. Pts were 19-78 years old (median 48.5). Grade 3 or 4 toxicities observed in >10% of cases included hepatotoxicity (81%, 47/58); antithrombin 3 depletion (72.4%, 42/58); hypofibrinogenemia <100 (58.6%, 34/58); hypertriglyceridemia (20.8%, 10/48); venous thromboembolism (12.1%, 7/58) and hemorrhage (12.1%, 7/58). Acute pancreatitis (8.6%, 5/58) and hypersensitivity (2/58, 3.4%) were less common. On univariate analysis, grade 3 liver injury was significantly associated with younger age groups (18-40 and 40-60 vs >60 years; p=0.025), likely due to older age strongly correlating (p <0.01) with receipt of <2000IU/m2 pegaspargase. No other toxicity was significantly associated with age. Hypofibrinogenemia and hepatotoxicity were significantly associated with initial receipt of pegaspargase during induction vs consolidation (p=0.042, p=0.013, respectively) but age was not. Pts receiving a max dose PEG of <2000IU/m2 had significantly lower odds of developing hepatotoxicity and hypertriglyceridemia than those receiving 2000 IU/m2 or more (p=0.008, p=0.003, respectively). On multivariate analysis, higher max dose of PEG received (2000 IU/m2 or over) correlated with greater odds of hepatotoxicity, hypertriglyceridemia and acute pancreatitis (OR 1.72, CI 1.23-2.38; OR 1.31, CI 2.18, CI 1.59-3.03; and OR 1.46, CI 1.13-1.88, respectively). Hypertriglyceridemia was also associated with older age and BMI >30 (OR 1.31, CI 1.05-1.62, and OR 1.31, CI 1.09-1.59, respectively). In summary, low dose pegaspargase is a viable option in ALL in adults over 60, with only hypertriglyceridemia associated with older age. Future work might correlate serum pegaspargase activity to intolerance and outcomes, and examine whether prophylactic treatment e.g. with levocarnitine might prevent toxicity. Citation Format: Yosef Joseph Rene Amel Riazat-Kesh, Hannah Levavi, Sangeetha Venugopal, Carli Beall, Ronald Hoffman, Marina Kremyanskaya, John Mascarenhas, Sara Kim, Michal Bar-Natan. Pegaspargase is a viable option in elderly adults with acute lymphoblastic leukemia. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5517.

Effects of post-transplant maintenance therapy with decitabine prophylaxis on the relapse for acute lymphoblastic leukemia.

In adults with acute lymphoblastic leukemia (ALL), post-transplant relapse is a major risk factor for mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our study investigated the efficacy and safety of decitabine (dec) with ALL patients post-transplantation. We performed a retrospective cohort study to assess the efficacy of decitabine (dec) with post-transplant ALL at the First Affiliated Hospital of Zhengzhou University from February 2016 to September 2021. A total of 141 consecutive ALL patients were analyzed and divided into decitabine (dec, n = 65) and control (ctrl, n = 76) groups based on whether they were treated with decitabine after allo-HSCT. The 3-year cumulative incidence of relapse (CIR) rate in the dec group was lower than that in the ctrl group (19.6 vs. 36.1%, p = 0.031), with a hazard ratio of 0.491 (95% confidence interval [CI], 0.257-0.936). Additionally, subgroup analyses revealed that the 3-year CIR rate of T-ALL and Ph-negative B-ALL patients in the dec and ctrl groups was 11.7 vs. 35.9% and 19.5 vs. 42.2% (p = 0.035, p = 0.068) respectively. In summary, ALL patients, especially those with T-ALL and Ph-negative B-ALL, may benefit from decitabine as maintenance therapy following allo-HSCT.

Reduced 8-Gray Compared to Standard 12-Gray Total Body Irradiation for Allogeneic Transplantation in First Remission Acute Lymphoblastic Leukemia: A Study of the Acute Leukemia Working Party of the EBMT

In this registry-based study, we compared outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) in adult patients with acute lymphoblastic leukemia (ALL) transplanted in first complete remission (CR-1), following conditioning with total body irradiation (TBI) at a standard 12-Gray or at a lower 8-Gray total dose. Patients received fludarabine (flu) as the sole chemotherapy complementing TBI. Eight-Gray TBI/flu was used in 494 patients and 12-Gray TBI/flu in 145 patients. Eighty-eight (23.1%) and 36 (29%) of the patients had Ph-negative B-ALL, 222 (58.3%) and 53 (42.7%) had Ph-positive B-ALL, 71 (18.6%) and 35 (28.2%) T-ALL, respectively (P = 0.008). Patients treated with 8-Gray were older than ones received 12-Gray (median 55.7 versus 40.3 years, P < 0.0001) and were more frequently administered in vivo T-cell depletion (71% versus 40%, P <0.0001). In a multivariate model adjusted for age, type of ALL, and other prognostic factors, leukemia-free survival (primary endpoint) as well as relapse, nonrelapse mortality, overall survival, and GVHD-free, relapse-free survival were not influenced by the TBI dose. These results were confirmed when we focused on patients <55 years of age (median 47 years). Patients with Ph-positive ALL or T-ALL had significantly better survival outcomes than ones with Ph-negative B-ALL, mainly due to significantly fewer relapses. We conclude that 8-Gray TBI is sufficient for adult patients with ALL transplanted in CR-1 with no additional benefit of augmenting the conditioning intensity to 12-Gray.

Outcomes of Hispanic Vs Non-Hispanic Philadelphia-like B Cell ALL Treated in the Central Valley of California

Background: Philadelphia-like B cell ALL (Ph-like ALL) accounts for a majority of poor outcomes in patients with Ph-negative B cell ALL (Ph- ALL). Ph-like ALL is a heterogeneous subgroup characterized by mutations that involve the tyrosine kinase and cytokine receptor signaling pathways. Prior studies have suggested an increased incidence of B-ALL in the Hispanic community may be attributable to a higher incidence of Ph-like ALL. This is clinically relevant as Ph-like ALL is associated with worse outcomes. Advances in molecular testing have identified Ph-like sub-classifications of at least 4 unique groups. Ph-like ALL outcomes have not been well reported following the approval of novel treatment options such as bispecific antibodies and CAR-T cell therapy. Our prior study in 2020 reported mutational distributions of 8 Ph-like ALL patients out of 16 Ph- ALL cases sequenced. This is a follow up analysis of Ph- ALL patients treated in Fresno, CA (49.6% Hispanic population) both before and after the adoption of novel therapies. Methods: Patients diagnosed with Ph negative B-ALL from 01-01-2008 to 12-31-2021 at Community Medical Centers were included. Patients with available tissue and without molecular sequencing at diagnosis were sequenced by Neo-Genomics (14 patients), Foundation Medicine Hematology (23), other NGS (3), and no sequencing available (14). Demographic and disease relevant information was collected. Data was collected on incidence of cytogenetic and molecular abnormalities, disease spread (CNS involvement, organ involvement), CD20% expression, number of mutations (n<3 vs. n≥3), and number of treatment lines. Chi-square or Fisher's exact test and contingency table were used to compare characteristics of patients with Ph-like mutations vs those without. Kaplan-Meier curves were utilized to compare median progression free survival (PFS) after 1st line therapy and median overall survival (OS). Results: A total of 48 patients were included. 23 patients had Ph-like mutation present vs 25 without. 18 Hispanic patients had Ph-like mutation vs 15 without (p=0.183). The Ph-like group had higher BMI (36.4 vs 30.7, p=0.033) and more patients with ≥3 mutations compared to the non-Ph-like group (p=0.018). The distribution of mutations within the Ph like group were: CRLF (44%), JAK-STAT (39%), ABL (13%), and EPOR/JAK-2 (4%). There were no significant differences between the Ph-like and non-Ph-like groups in mean age at diagnosis (40.1 vs 35 years, p=0.27), CNS disease at diagnosis (17.4% vs 11.5%, p=0.350), CD20+ disease (17.4% vs 30.8%, p=0.098), complete response rates (60.9% vs 70.3%, p=0.223), or median PFS after 1st line therapy (284 vs 467 days, p=0.164). The non-Ph-like group had significantly higher median OS vs the Ph-like group (680.5 vs 377 days, p=0.018). Within the Ph-like group, Hispanic vs non-Hispanic patients did not differ significantly in terms of PFS after 1st line therapy (p=0.426) or OS (p=0.287). Survival analysis of patients before vs during/after the year 2017 showed significantly higher median PFS after 1st line therapy in patients treated during/after 2017 than before (1721 vs 631 days, p=0.037), however without significant median OS difference (1097 vs 819 days, p=0.712). There was no significant median PFS (p=0.166) or OS (p=0.731) difference among Ph-like patients treated before vs during/after 2017. Novel agent use in our study: 8/12 patients (Blinatumomab 7, Inotuzumab 1), 6/9 patients (Blinatumomab 2, Inotuzumab 2 CAR- T 1), 2/3 patients (Inotuzumab 2) in second, third and fourth line respectively. Conclusions: Ph-like ALL patients had worse OS outcomes compared to non-Ph-like patients. A significant proportion of both Ph-like and non-Ph-like patients consisted of Hispanics, confirming the high incidence of B-ALL in this ethnic subgroup reported in prior studies. Our Ph-like patients had significantly higher BMI and number of mutations which could be contributing factors to their worse outcomes compared to non-Ph-like patients. Those treated during/after 2017 had significantly improved PFS after induction; this could be due to the FDA approval of novel agents beginning that year. This however did not translate to a significant OS benefit regardless of Ph-like status. Overall, these results re-emphasize the need for further research involving ethnic subgroups and novel therapies for this high-risk and heterogeneous disease. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Risk Factors Influencing Transplant Outcomes of Adults with Acute Lymphoblastic Leukemia in First Complete Remission: A Retrospective Analysis from the ALWP of the EBMT

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) remains a standard of care for adult patients with acute lymphoblastic leukemia (ALL) at high risk of relapse, i.e. high-risk features at time of diagnosis (ex. Philadelphia (Ph) positive ALL), or detectable minimal residual disease (MRD+). The aim of our study was to identify risk factors influencing transplant outcomes in ALL patients transplanted between 2015 and 2021. Methods: We included adults undergoing allo-HSCT for ALL in CR1 with available data of ALL phenotype, Ph-status, and MRD pre-transplant. All donor types and stem cell sources were eligible, except cord blood. Ex-vivo T-cell depletion (TCD) represented an exclusion criterion. Results: We identified 2349 transplanted patients including 870 from HLA-matched sibling (MSD), 1150 from unrelated (79% 10/10 and 21% 9/10 UD), and 329 from haploidentical donors (Haplo). Median age was 42.6 (range 18-76.1) years. Median follow-up was 23.5 (95% CI 21.8-24.2) months. The entire cohort was composed of 667 patients (28.4%) with Ph-negative B-ALL, 1325 (56.4%) with Ph-positive B-ALL and 357 (15.2%) with T-ALL. Median time from diagnosis to allo-HSCT was 5.8 (range 1.3-18) months. Stem cell source was peripheral blood (PB) in 85.3% of cases. Conditioning regimen was reduced-intensity (RIC) in 21% and myeloablative (MAC) in 79% of cases. Total body irradiation (TBI) was used in 65.8% of patients, mostly as a MAC (93.9%). Pre-transplant MRD+ was reported in 35.4% while in-vivo TCD was used in 51.5% of cases. At 180 days, cumulative incidence of grade II-IV and grade III-IV acute graft-versus-host disease (aGVHD) were 29.2% (95% CI 27.3-31.1) and 10.1% (95% CI 8.9-11.4), respectively. Two-years overall and extensive chronic GVHD (cGVHD) were 34% (95% CI 31.7-36.3) and 15% (95% CI 13.2-16.8), respectively. At two years, relapse incidence (RI), non-relapse mortality (NRM), leukemia-free survival (LFS), overall survival (OS) and GVHD-free/relapse free survival (GRFS) were 22.2% (95% CI 20.3-24.2), 15.4% (95% CI 13.8-17.1), 62.3% (95% CI 60-64.6) 73.9% (95% CI 71.7-76) and 48% (95% CI 45.6-50.3), respectively. By multivariate analysis, MSD (reference group) was associated to higher RI compared to 9/10 UD (HR 1.47, 95% CI 1.01-2.12; p<0.05) and Haplo (HR 1.64, 95% CI 1.15-2.27; p<0.01) but lower NRM and grade II-IV aGVHD compared to both 9/10 and 10/10 UD (for NRM HR 0.54, 95% CI 0.36-0.81; p<0.01 and HR 0.65, 95% CI 0.48-0.88; p<0.01; for aGVHD: HR 0.58, 95% CI 0.44-0.78; p<0.01 and HR 0.70, 95% CI 0.56-0.87; p<0.01). Compared to Ph-negative ALL (reference group), Ph-positive ALL was associated with a lower RI (HR=0.61, 95% CI 0.49-0.77; p<0.01) and higher LFS (HR=0.71, 95% CI 0.60-0.85; p<0.01), OS (HR=0.59, 95% CI 0.48-0.72; p<0.01) and GRFS (HR=0.81, 95% CI 0.70-0.94; p<0.01), while T-ALL was associated to lower NRM (HR 0.58, 95% CI 0.37-0.91: p<0.02) and cGVHD (HR 0.73, 95% CI 0.54-0.98; p<0.04). MRD+ group faced higher RI (HR=1.74, 95% CI 1.42-2.12; p<0.01), lower LFS (HR=1.41, 95% CI 1.21-1.65; p<0.01), OS (HR=1.31, 95% CI 1.08-1.58; p<0.01) and GRFS (HR=1.31, 95% CI 1.14-1.49; p<0.01). Use of TBI enabled lower RI (HR 0.78, 95% CI 0.61-0.99; p=0.04), higher LFS (HR=0.80, 95% CI 0.67-0.96; p<0.02) but higher grade II-IV aGVHD (HR 1.54, 95% CI 1.23-1.92; p<0.01) and cGVHD (HR 1.47, 95% CI 1.16-1.87; p<0.01) compared to chemotherapy. Patients receiving a RIC had a higher RI (HR=1.52, 95% CI 1.17-1.98; p<0.01) and a lower NRM (HR=0.55, 95% CI 0.39-0.77; p<0.01). In vivo TCD allowed lower risk of cGVHD (HR=0.69, 95% CI 0.55-0.85; p<0.01) and higher GRFS (HR=0.78, 95% CI 0.66-0.91; p<0.01). PB stem cells and female-donor to male-recipient were independently associated to higher risk of cGVHD. Elderly patients faced lower LFS, OS and GRFS. Conclusions: Our study reported overall favorable outcomes in the population of recently allografted patients with ALL in CR1 (LFS> 60% et OS> 70% at 2 years). Prognostic role of pre-transplant MRD is confirmed. Results in Ph-positive ALL are not inferior compared to Ph-negative ALL, most probably due to the use of tyrosine kinase inhibitors. Whether incorporation of novel agents will change the role of allo-HSCT in Ph-positive ALL is under investigation. Use of TBI and HLA mismatches are both associated with lower RI despite a higher risk of GVHD, highlighting the importance of tailoring GVHD prophylaxis in these settings.

Updated Outcomes of the University of Southern California (USC) ALL Frontline Regimen (based on CCG-1882) after Protocol Modification in the Era of Novel Agents in Ph-Negative ALL Patients

INTRODUCTION: Pediatric inspired regimens in adolescent young adults and adults have improved outcomes in acute lymphoblastic leukemia (ALL). CALGB 10403 was prospectively tested in patients 17-39 years and achieved a 3-year event free survival of 59%. In 2007, we reported outcomes after incorporating peg-asparaginase (PEG) dosed at 2000mg/m in induction for patients aged 17- 55 years. This was well tolerated and achieved a complete remission (CR) rate of 96%. In 2014, we reported experience with the use of multiple doses of PEG (CCG-1882) for newly diagnosed ALL adult patients achieving a 7-year overall survival (OS) of 51%. Since then, the USC ALL regimen consisting of 2 induction phases, was further modified with a goal of maintaining good outcomes and improving compliance and toxicities. Fractionated doses of cytarabine were changed to a single dose, the methotrexate dose of 1g/ m2 (2.5 g/m2 if T cell) given D1,15 in intensification phases was changed to 3g/ m2 (B and T cell) given in single doses, and consolidation was increased to six cycles allowing for PEG holidays. Moreover, the approval and incorporation of novel agents such as blinatumomab and inotuzumab also changed outcomes in ALL. Therefore, this study reports an update of outcomes since further modification of the USC ALL pediatric-based regimen in the era of novel agents. METHODS: This is a retrospective review which included adults aged 18 years with newly diagnosed Philadelphia negative ALL (2016-2020) treated at the USC/Norris Comprehensive Cancer Center and the Los Angeles County Hospital (LAC). Primary objectives were over-all survival (OS), event-free survival (EFS), disease-free survival (DFS) at 3 years. Secondary outcomes were complete remission/complete remission with incomplete recovery (CR/CRi) and minimal residual disease (MRD) by flow cytometry rates. OS, DFS, EFS were reported through Kaplan Meier curves and Log-rank tests. Two-sided p value ≤0.05 was significant. RESULTS: 121 patients with Ph-negative ALL were reviewed (49.6% Ph-negative B-ALL, 23.9% Ph-like B-ALL, 0.8% B cell lymphoblastic leukemia (LBL), 9.1% T cell ALL, 4.1% T cell LBL, 4.1% early T-cell, 5.8% mixed phenotype acute leukemia (MPAL). Median age at diagnosis was 39.3 years. There were 71.9% Hispanic, 15.7% White, 9.9% Asian, 2.5% African Americans. 57.9% males, 42.1% females. In terms of risk stratification, the majority were unfavorable at 54.6% and 37.8% unknown. Median BMI was 29.6 kg/ m2. 52.5% had hepatic steatosis and 5% had CNS disease pre-induction. 68.7% received PEG during induction 1, and 67.9% during induction 2. Post-induction 1, 83.5% patients achieved CR/Cri with 49% MRD negativity by flow. Post-induction 2, 75% achieved CR/Cri with 57.1% MRD negativity by flow. 26.4% received blinatumomab but not allo-HSCT. 20% received blinatumomab and underwent allo-HSCT. 34.7% received blinatumomab for MRD flow positivity, median 2 cycles, only 5.8% received inotuzumab, 35.5% underwent allogenic stem cell transplant. 28.9% and 9.1% had any relapse and refractory disease, respectively. Mortality rate was at 14.9%. 3y OS was at 80.7%, 3y EFS at 54.3% and 3y DFS 61.3%. When stratified by MRD flow negativity after induction 1 and 2, 3y OS was 83.7% vs 91.1% (p=0.55), 3y DFS was 68% vs 64.1%(p=0.98) and 3y EFS was 68% vs 59.5% (p=0.84). When stratified by blinatumomab use, 3y OS 72.5% vs 85.1% (p=0.15), 3y EFS was 31.6% vs 67.5% (p=0.001), 3y DFS was 40.1% vs 73.1% (p=0.001) (Fig 1-2). Use of PEG resulted in grade 3/4 toxicities including hypersensitivity (4.1%), transaminitis (21.5%), pancreatitis (5.4%), hypertriglyceridemia (49.5%), hypofibrinogenemia (45.5%), hyperbilirubinemia (21.5%) and thrombosis (16.5%). CONCLUSIONS: The modified pediatric-based USC ALL induction regimen using PEG maintained a high 3y OS at 85.3% and appreciable 3y EFS at 54.3% and 3y DFS at 61.3%, with tolerable toxicities in an era of novel agents like blinatumomab. This compares favorably with the original USC ALL regimen, CALGB 10407 and GRAALL 2005. Of note, 3y EFS and 3y DFS were significantly lower in those who underwent blinatumomab since these patients were MRD flow positive and lacked deeper remissions, but 3y OS (72.5%) remained high regardless, even though 26.4% who received blinatumomab were not able to go for allo-HSCT. This suggests the beneficial effect of blinatumomab. Further follow-up is necessary to provide a more robust and mature survival data. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Dynamics of minimal residual disease defines a novel risk-classification and the role of allo-HSCT in adult Ph-negative B-cell acute lymphoblastic leukemia

The prognosis of minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL) patients is well established. However, the implementation of dynamic MRD for risk classification and decision-making for allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains vague. In this study, we collected multiparameter flow cytometry (MFC)-MRD data of Ph-negative B-ALL patients (n = 134) from the Precision-Classification-Directed-Target-Total-Therapy-ALL-2016 (PDT-ALL-2016) cohort and stratified it into high-(HR), medium-(MR), and standard-risk (SR) groups. With a median of 3.65 years follow-up (95% CI: 3.037–4.263), 3-year OS rate was 51.8 ± 8.3% in HR, compared with MR 61.5 ± 10.8% (p = 0.472), and SR 73.3 ± 5.9% (p = 0.006). Multivariate analysis shows that integrated dynamic MRD is an independent factor for overall survival. Compared to pediatric-inspired chemotherapy, allo-HSCT significantly improves the survival of the HR cohort (p < 0.001), but not in MR and SR. Finally, our study suggests that integrated dynamic MRD defines a novel risk-classification criteria and highlights the benefits of allo-HSCT in adult patients with Ph-negative ALL.

Allogeneic Hematopoietic Stem Cell Transplantation for Adult Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia in Second Complete Remission

Even in the era of high-intensity chemotherapy, disease recurrence remains a major cause of treatment failure in adult patients with Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia (Ph-negative B-ALL). For patients who achieved second complete remission (CR2) with salvage chemotherapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) could be the best curative treatment. However, limited data are available on the outcomes of allo-HSCT for adult Ph-negative B-ALL in CR2 in the high-intensity chemotherapy era. We evaluated the transplantation outcomes of adult patients with Ph-negative B-ALL in CR2 compared with those in CR1. We also clarified the prognostic factors among adult allo-HSCT recipients with Ph-negative B-ALL in CR2. We conducted a nationwide retrospective study using the data form Japanese transplant registry database. Patients aged ≥16 years and underwent their first allo-HSCT between 2003 and 2017 were included. The 3-year overall survival (OS) rate of the patients in CR2 (n=382) was significantly lower than that in first complete remission (n=1375) (51.8% versus 68.1%; P < .001), accompanied by a higher relapse rate (34.2% versus 17.6% at 3 years; P < .001). In a multivariate analysis among CR2 patients, time from diagnosis to allo-HSCT (≤2 years) was a significant factor for OS (hazard ratio [HR] 1.87; P < .001) and relapse (HR=1.88; P < .001), whereas age at allo-HSCT (≥30 years) was a significant factor for OS (HR=2.10, P < .001) and nonrelapse mortality (HR=2.68; P < .001). By assigning a score of 1 to each factor, the 3-year OS rate of CR2 patients significantly stratified: 70.7% in patients with score 0, 56.4% with score 1, and 28.4% with score 2 (P < .001). The survival outcomes of allo-HSCT in adult Ph-negative B-ALL patients in CR2 were inferior to those in CR1 in the high-intensity chemotherapy era, mainly because of the higher relapse rate. Among the CR2 patients, the short time between diagnosis and allo-HSCT was a significant risk factor for disease recurrence and overall mortality. Better disease control with novel treatment strategies may be needed for early relapse. In addition, the nonrelapse mortality rate in patients over 30 years of age was particularly high among CR2 patients, suggesting the need for improved supportive care for these patients. Further studies are warranted on the outcomes of allo-HSCT after achieving CR2 with novel drugs, such as inotuzumab ozogamicin and blinatumomab.

Nonmyeloablative Allogeneic Transplantation in First Remission for Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia with Post-Transplantation Cyclophosphamide: Outcomes By Receipt of Pre-Transplant Blinatumomab

Nonmyeloablative Allogeneic Transplantation in First Remission for Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia with Post-Transplantation Cyclophosphamide: Outcomes By Receipt of Pre-Transplant Blinatumomab

An Update on Outcomes Using the USC ALL Frontline Regimen (based on CCG-1882) after Further Modification of Protocol in the Era of Novel Agents in Ph-Negative ALL Patients; A Retrospective Study

▪INTRODUCTION: The use of pediatric inspired regimens in adolescent young adults and adults has improved outcomes in acute lymphoblastic leukemia (ALL). CALGB 10403 was prospectively tested in patients 17-39 years, showing a 3-year event free survival of 59%.In 2007, our institution reported outcomes after incorporating peg-asparaginase (PEG) dosed at 2000mg/m 2 in induction for patients aged 17- 55 years. This regimen was well tolerated and resulted in a complete remission (CR) rate of 96%. In 2014, we reported experience with the use of multiple doses of PEG (CCG-1882) for newly diagnosed ALL adult patients, with a 7-year overall survival (OS) of 51%. Since our last report, the USC ALL regimen consisting of 2 induction phases, has been further modified with a goal of maintaining good outcomes, and improving compliance and toxicities. Fractionated doses of cytarabine were changed to a single dose, the methotrexate dose of 1g/m 2 (2.5 g/m 2 if T-cell) given D1,15 of intensification phases was changed to 3g/m 2 (B and T cell) given in single doses, and consolidation was increased to six cycles allowing for PEG holidays (Table 1).Moreover, the approval and incorporation of novel agents such as blinatumomab and inotuzumab also changed outcomes in ALL. Therefore, this study reports an update of outcomes since further modification of the USC ALL pediatric-based regimen in the era of novel agents. METHODSThis is a retrospective review which included adults aged >18 with newly diagnosed Philadelphia negative ALL between 2016 and 2020 treated at USC/Norris Cancer Center and Los Angeles County Hospital (LAC). Primary objectives were over-all survival (OS), event-free survival (EFS), disease-free survival (DFS) at 3 years, and secondary outcomes were complete remission/complete remission with incomplete recovery (CR/CRi) rates and minimal residual disease (MRD) by flow cytometry. OS, DFS, EFS were reported through Kaplan Meier curves and Log-rank tests. Two-sided p value ≤0.05 was significant.RESULTS: 121 patients with Ph-negative ALL were identified (49.6% Ph-negative B-ALL, 24% Ph-like B-ALL, 0.8% B cell lymphoblastic leukemia (LBL), 9.1% T cell ALL, 4.1% T cell LBL, 4.1% early T-cell, 5.8% mixed phenotype acute leukemia (MPAL). Median age at diagnosis was 38.5 years and maximum age of patient to receive pegasparagase during induction 1 was 63 years. 71.9% Hispanic, 15.7% white, 9.9% Asian, 2.5% African American. 57.9% males, 42.1% females. 3.4% were favorable, 4.2% intermediate, 54.6% unfavorable and 37.8% unknown by karyotypic risk stratification. Median BMI was 28.9 kg/m 2.54.6% had hepatic steatosis either on history or imaging and 5.1% had CNS disease pre-induction.Post-induction 1, 81.4% of patients achieved CR/CRi and 50% MRD negative. Post induction 2, 82.2% achieved CR/CRi, 67.7% MRD flow negative. Post-consolidation 1, 90.9% were MRD flow negative. 33.1% subsequently received blinatumomab for MRD positive disease, 5% given inotuzumab for relapsed disease, 32.2% underwent allogenic hematopoietic stem cell transplant (allo-HSCT). Median number of pegasparagase doses received during treatment was 2, rate of relapse and mortality was 27.3% and 13% respectively.Median OS and DFS were not reached but median EFS was 35 months. 3-year OS was 85.3%, when stratified according to MRD post induction 2; 3-year OS was 91.7% for MRD positive patients and 91.2% for MRD negative patients (p=0.55). 3-year DFS was 83.2%; 88.2% for MRD positive patients and 97.4% for MRD negative patients (p=0.22). 3-year EFS was 47.3%; 51.3% for MRD positive patients and 50.6% for MRD negative patients (p=0.49) (Tables 2-3).Use of pegasparagase resulted in grade 3/4 toxicities including hypersensitivity (4.1%), transaminitis (21.5%), pancreatitis (5.4%), hypertriglyceridemia (49.5%), hypofibrinogenemia (45.5%), hyperbilirubinemia (21.5%) and thrombosis (16.5%). CONCLUSIONSPediatric-based modified USC ALL induction regimen led to a high 3-year OS (85.3%), DFS (83.2%) and EFS (47.3%) with predictable toxicity and compares favorably with original USC ALL regimen, CALGB 10407, GRAALL 2005 and USC/MSKCC regimen.Interestingly, MRD positivity after induction 2 did not adversely affect OS, DFS or EFS, which is likely due to incorporation of blinatumomab and inotuzumab. These agents could have allowed for deeper remissions allowing Ph-negative patients with residual disease to receive allo-HSCT. [Display omitted] DisclosuresChaudhary: Oncotartis: Consultancy; Pancella: Consultancy; Moderna: Current equity holder in publicly-traded company; Celldex: Current equity holder in publicly-traded company; TCR2: Current equity holder in publicly-traded company; Allogene: Current equity holder in publicly-traded company; Athelas: Consultancy, Current holder of stock options in a privately-held company; Angeles Therapeutics: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Founder, Patents & Royalties: Cell therapy . Douer: Servier: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Adaptive: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Speakers Bureau; Jazz: Consultancy. Yaghmour: Novartis: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Alexion: Speakers Bureau; Astellas: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Jazz: Speakers Bureau; Agios: Consultancy, Speakers Bureau.