Diagnosis Of B-cell Acute Lymphoblastic Leukemia Research Articles

Changes in RANKL, OPG, and 25(OH)D Levels in Children with Leukemia from Diagnosis to Remission.

The receptor activator of the nuclear factor-kB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) pathway is a determining pathway in the balance between bone formation and resorption, and disruptions in this complex can affect bone metabolism. This study analyzes the changes in RANKL, OPG, and 25(OH)D levels; the RANKL/OPG ratio; and other bone turnover markers (BTMs) from diagnosis to complete remission in children with acute lymphoblastic leukemia (ALL). This is a prospective observational cohort study, carried out at the Instituto Mexicano del Seguro Social, Mexico City, including 33 patients (4-17 years) with newly diagnosed B-cell ALL. The patients were treated with the HP09 chemotherapy protocol. Children who had previously been treated with corticosteroids were excluded. A peripheral blood sample at diagnosis and remission was collected to determine the 25(OH)D and BTM concentrations. Increased RANKL (p = 0.001) and osteocalcin (p < 0.001) levels and RANKL/OPG ratio (<0.001) and a decreased OPG level (p = 0.005) were observed at remission, predominantly in the high-risk (HR) relapse and vitamin D deficiency groups. A negative association between RANKL and OPG (r = -0.454, p = 0.008) was observed. we suggest that the RANKL/OPG ratio could serve as a bone remodeling marker in ALL patients.

Impact of Age on Pharmacogenomics and Treatment Outcomes of B-Cell Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) can occur across all age groups, with a strikingly higher cure rate in children compared with adults. However, the pharmacological basis of age-related differences in ALL treatment response remains unclear. Studying 767 children and 309 adults with newly diagnosed B-cell ALL enrolled on frontline trials at St Jude Children's Research Hospital, MD Anderson Cancer Center, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group, we determined the ex vivo sensitivity of leukemia cells to 21 drugs. Twenty-three ALL molecular subtypes were identified using RNA sequencing. We systematically characterized the associations between drug response and ALL genomics in children, adolescents and young adults, and elderly adults. We evaluated the effect of age-related gene expression signature on ALL treatment outcomes. Seven ALL drugs (asparaginase, prednisolone, mercaptopurine, dasatinib, nelarabine, daunorubicin, and inotuzumab ozogamicin) showed differential activity between children and adults, of which six were explained by age-related differences in leukemia molecular subtypes. Adolescents and young adults showed similar patterns of drug resistance as older adults, relative to young children. Mercaptopurine exhibited subtype-independent greater sensitivity in children. Transcriptomic profiling uncovered subclusters within CRLF2-, DUX4-, and KMT2A-rearranged ALL that were linked to age and cytotoxic drug resistance. In particular, a subset of children had adult-like ALL on the basis of leukemia gene expression patterns across subtypes, despite their chronological age. Resistant to cytotoxic drugs, children with adult-like ALL exhibited poor prognosis in pediatric ALL trials, even after adjusting for age and minimal residual diseases. Our results provide pharmacogenomic insights into age-related disparities in ALL cure rates and identify leukemia prognostic features for treatment individualization across age groups.

Diagnostic significance of cerebrospinal fluid flow cytometry in Chinese children with B lineage acute lymphoblastic leukemia

BackgroundCentral nervous system leukemia (CNSL) is one of the major causes of the poor prognosis of childhood leukemia. We aimed to compare the sensitivity of cytomorphology (CM) and flow cytometry (FCM) in diagnosing CNSL, emphasizing the importance of FCM in the diagnosis process.MethodsOne-hundred-sixty-five children with newly diagnosed B-cell Acute Lymphoblastic Leukemia (B-cell ALL) were included in this study. Cerebrospinal fluid (CSF) samples were taken for routine CSF analysis, CM analysis, and FCM examination. Computed tomography scans and/or magnetic resonance imaging were performed at diagnosis. Patients with CNS2, CNS3, and traumatic lumbar puncture (TLP) at diagnosis received two additional courses of triple intrathecal injections during induction treatment. We compared the sensitivity of FCM and CM in the diagnosis of children with CNSL.ResultsOne hundred and twenty-eight (77.58%) CSF samples were negative by either CM or FCM (CM−/FCM−), four (2.42%) were positive by both CM and FCM (CM+/FCM+), and thirty-three (20%) displayed a single positive finding by FCM (CM−/FCM+) (p = 0.044). By adding two intrathecal injections in the induction treatment, ten children with TLP+ had no CNS relapse, like those with TLP−. However, compared to CNS1 and TLP, the event-free survival (EFS) did not significantly improve in patients with CNS2 and CNS3. Moreover, CNSL status was associated with worse 3-year EFS (p < 0.05).ConclusionsWe have validated that FCM is more accurate in stratifying the status of the CNS compared to CM analysis. However, to improve the EFS rate of childhood leukemia, it is necessary to combine CM examination, FCM, and cranial imaging for the early diagnosis of CNSL.

Reduced-dose chemotherapy followed by blinatumomab in induction therapy for newly diagnosed B-cell acute lymphoblastic leukemia.

Blinatumomab early-line treatment in B-cell precursor acute lymphoblastic leukemia (B-ALL) might improve clinical outcomes. We conducted a retrospective real-world cohort analysis in 20 newly diagnosed B-ALL patients who received reduced-dose chemotherapy (idarubicin, vindesine, and dexamethasone) for 1-3 weeks, followed by blinatumomab for 1-4 weeks as an induction therapy. At the end of the induction therapy, a complete remission rate of 100% was achieved; 17 (85%) patients were minimal residual disease (MRD) negative (<1 × 10-4 ). Adverse events (AEs) were reported in 12 (60%) patients-43.8% were grade 1-2 and 56.2% were grade 3-4. No incidence of neurotoxicity or grade ≥3 cytokine release syndrome was reported. Blinatumomab demonstrated a significant improvement in clinical outcomes in patients with newly diagnosed B-ALL irrespective of their poor-risk factor status and the pretreatment blast burden.

Dose-Dense Mini-Hyper-CVD, Inotuzumab Ozogamicin and Blinatumomab Achieves Rapid MRD-Negativity in Philadelphia Chromosome-Negative B-cell Acute Lymphoblastic Leukemia

BackgroundThe combination of low-intensity chemotherapy and inotuzumab ozogamicin (INO), with sequential blinatumomab, is highly effective in older adults with newly diagnosed B-cell acute lymphoblastic leukemia (ALL) and in relapsed or refractory B-cell ALL. Earlier, “dose-dense” administration of blinatumomab could lead to earlier and deeper measurable residual disease (MRD) responses and better outcomes. Patients and MethodsWe performed a retrospective analysis of the safety and efficacy of a dose-dense regimen of mini-hyper-CVD (mini-hyperfractionated cyclophosphamide, vincristine, and dexamethasone alternating with mini-methotrexate and cytarabine), INO, and blinatumomab in patients with B-cell ALL. ResultsTwenty-one patients were treated (frontline, n = 9; MRD consolidation, n = 4; relapsed/refractory, n = 8). In the frontline cohort, all patients achieved CR/CRi and MRD negativity by flow cytometry at the end of cycle 1. Across the frontline and MRD consolidation cohorts, 10/11 patients (91%) achieved next-generation sequencing MRD negativity at a sensitivity of 10−6, including 6/10 evaluable patients (60%) who achieved next-generation sequencing MRD negativity after cycle 1. The CR/CRi rate in the relapsed/refractory cohort was 63%, and all responders achieved MRD negativity by flow cytometry at the end of cycle 1. The 1-year overall survival rate for the combined cohort of the frontline and MRD-positive patients was 83%. No new safety signals were observed with the dose-dense mini-hyper-CVD, INO, and blinatumomab regimen. ConclusionDose-dense delivery of mini-hyper-CVD, INO, and blinatumomab was safe and resulted in rapid and deep MRD negativity in patients with B-cell ALL. This regimen is now being prospectively evaluated in both the frontline and relapsed/refractory settings.

Updated Results from a Phase II Study of Hyper-CVAD, with or without Inotuzumab Ozogamicin, and Sequential Blinatumomab in Patients with Newly Diagnosed B-Cell Acute Lymphoblastic Leukemia

Background Blinatumomab improves overall survival (OS) compared with chemotherapy in patients (pts) with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and is also FDA-approved for eradication of persistent or recurrent measurable residual disease (MRD). Blinatumomab also improves OS when added to standard chemotherapy, irrespective of MRD status, in newly diagnosed Philadelphia chromosome (Ph)-negative B-cell ALL. Inotuzumab ozogamicin (INO) improves OS in the relapsed/refractory setting, and we hypothesized that the addition of INO to hyper-CVAD plus blinatumomab would lead to deeper and more durable responses, reduce relapses, and improve survival. Methods In this phase II study, pts age 14-59 with newly diagnosed Ph-negative B-cell ALL, including pts who had received no more than 1 prior cycle of chemotherapy, were eligible. Pts had to have a performance status of ≤3, total bilirubin ≤2 mg/dl, creatinine ≤2 mg/dl, and no significant CNS pathology (except for CNS leukemia). Pts received hyper-CVAD alternating with high-dose methotrexate (MTX) and cytarabine (Ara-C) for up to 4 cycles, followed by 4 cycles of blinatumomab at standard doses. Pts with CD20+ disease (≥1% cells) received 8 doses of ofatumumab (2000 mg) or rituximab (375 mg/m2). Eight doses of prophylactic IT chemotherapy were given. Maintenance was with alternating blocks of POMP (given in maintenance cycles 1-3, 5-7, 9-11, and 13-15) and blinatumomab (given in maintenance cycles 4, 8, and 12). Those with high-risk disease features started blinatumomab after 2 cycles of hyper-CVAD. Beginning with pt #39, INO at a dose of 0.3 mg/m2 on day 1 and 8 was added to the 2 cycles of MTX/Ara-C (which was also dose reduced to 500 mg/m2 of MTX and 1 g/m2 of Ara-C with this amendment) and to 2 cycles of blinatumomab consolidation (4 total cycles with INO). Results As of June 2023, 75 pts have been treated (38 without INO and 37 with INO). Pt characteristics are shown in Table 1. The median age across both cohorts was 33 (range, 18-59). 36 pts (48%) had ≥1 high-risk pretreatment characteristic at enrollment (e.g. poor-risk cytogenetics, CRLF2 overexpression by flow and/or TP53 mutation). Sixteen pts were in complete remission (CR) at enrollment after 1-2 cycles of off-protocol therapy, 10 of whom were MRD-negative by 6-color flow cytometry. All 59 pts (100%) with active disease upon study entry achieved CR, with 50 pts (84%) achieving CR after the first cycle. MRD negativity by flow (sensitivity 10 -4) was achieved in 60 of 65 evaluable pts (92%), with 43 pts (66%) achieving flow MRD negativity after the first cycle. Two of the 5 patients who did not achieve flow MRD negativity had NUP214::ABL1 fusion, 1 had KMT2A rearrangement, and 2 are still early in treatment and have not yet received blinatumomab. Overall, 25 of 36 tested pts (69%) achieved next-generation sequencing-based MRD negativity at a sensitivity of 10 -6. The median duration of follow-up is 26 months (range, 1-77 months). Overall, 8 pts (11%) relapsed in the absence of SCT, 23 pts (31%) underwent stem cell transplantation (SCT) in first remission (2 of whom relapsed post-SCT), 3 pts (4%) died in CR, and 41 pts (55%) remain in continuous remission without SCT. Among the 10 relapses, 3 were in the CNS, 2 of which were CNS-only. All but one relapse occurred in pts with ≥1 poor-risk feature(s). Across both cohorts, the estimated 3-year OS was 88% and the 3-year relapse-free survival (RFS) was 79% . The 3-year OS rate for pts without a high-risk baseline feature was 93% vs 83% in pts with ≥1 high-risk feature. In a landmark analysis, there was no difference in outcomes between pts who underwent SCT in first remission versus those who did not (3-year OS: 90% versus 87%). With a median follow-up of 18 months in the INO group, 3 pts (8%) have relapsed, 2 with CNS-only relapses, and none have died. The 18-month RFS in the cohorts with and without INO were 92% vs 76% (p=0.18), and the OS was 100% vs 84% (p=0.04) ( Figure 1). One pt discontinued blinatumomab due to a related adverse event (grade 2 encephalopathy and dysphasia). No pts discontinued INO due to toxicity, and no cases of veno-occlusive disease have been observed.

“Dose-Dense” Mini-Hyper-CVD, Inotuzumab Ozogamicin and Blinatumomab Achieves High Rates of Rapid MRD-Negativity in Patients with Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia: A Retrospective Analysis

Background: Mini-hyper-CVD plus inotuzumab ozogamicin (InO) followed by sequential blinatumomab (Blina) is effective in both older adults with newly diagnosed B-cell ALL and in relapsed/refractory disease. We hypothesized that concomitant administration of these agents in a “dose-dense” (DD) fashion would also be safe and effective in B-cell acute lymphoblastic leukemia (ALL), leading to rapid measurable residual disease (MRD) negativity. Methods: This is a retrospective analysis of patients (pts) with B-cell ALL who received DD mini-hyper-CVD + InO + Blina outside of a clinical trial. All pts received mini-hyper-CVD alternating with mini-methotrexate and cytarabine in combination with InO. To be evaluable for this analysis, Blina must have started prior to day 21 of the first cycle of therapy. Pts were included if they received this regimen for 1.) frontline induction, 2.) treatment of MRD-positive remission, or 3.) salvage therapy for relapsed/refractory (R/R) disease. Results: Between 7/2020 and 1/2023, 21 eligible pts were treated (Table 1 ). The median age was 48 years (range, 6-74 years); 3 pts (all in the R/R cohort) were &amp;lt;18 years old. 9 pts (43%) were treated as frontline therapy, 4 (19%) for treatment of MRD (3 for flow-positive MRD and 1 for persistent FISH for t[4;11]), and 8 (38%) for R/R disease. In the MRD cohort, 3 pts were in first CR and 1 was in second CR; 1 pt received prior InO and 1 had prior allogeneic stem cell transplant (alloSCT). In the R/R cohort, pts were heavily pretreated, with a median number of prior therapies of 3 (range, 1-7); 2 pts received prior InO, 3 pts received prior Blina, 3 pts had undergone prior allo SCT, and 3 pts had received prior chimeric antigen receptor T-cell (CAR-T cell) therapy. Three pts (all in the R/R cohort) had extramedullary (EM) disease, 2 outside of the CNS without marrow disease and 1 with CNS disease and bone marrow MRD by flow. Pts received a median of 2 cycles (range, 1-5) of a dose-dense regimen. All pts received 0.9 mg/m 2 InO in cycle 1, except for 1 pt in the R/R cohort who received 0.6 mg/m 2 due to myelosuppression with prior InO. Themedian cumulative dose of InO was 1.2 mg/m 2 (range, 0.6-2.7 mg/m 2). Blina was started on a median of day 4 (range, day 4-17) of the first cycle of chemotherapy. Blina was started by day 7 in 16 pts (76%). In the frontline cohort, all pts (100%) achieved CR/CRi (CR in 8 pt and CRi in 1 pt), all after cycle 1 ( Table 2). All pts in the frontline cohort achieved flow MRD negativity. 7 pts were evaluable for bone marrow next generation sequencing (NGS) MRD (sensitivity 10 -6). Of these, 4/6 (67%) achieved NGS MRD negativity after cycle 1, and all 7 evaluable pts (100%) achieved NGS MRD negativity. In the MRD cohort, all 3 flow-positive pts became flow MRD negative after cycle 1; the pt with positive FISH for t(4;11) became FISH-negative after cycle 2. 3 of the 4 pts in the MRD cohort (75%) became NGS MRD negative. Overall, 5 of the 8 pts (63%) in the R/R cohort achieved CR/CRi. Among 5 evaluable pts in the R/R cohort with marrow disease (including the pt with CNS disease and MRD-positive marrow), all achieved flow MRD negativity after cycle 1. Overall, 7 pts (33%) underwent consolidative alloSCT (2 in the MRD cohort and 5 in the R/R cohort), and 1 pt in the MRD cohort underwent consolidative CAR-T cell therapy. The treatment regimen was well tolerated. No patients developed sinusoidal obstruction syndrome/veno-occlusive disease. One pt had grade 1 CRS, and 2 pts had grade 1 tremor. With a median follow-up of 13.4 months (range, 0.5-20.6 months), 6 pts (29%) have died (1 in the frontline cohort, 1 in the MRD cohort and 4 in the R/R cohort). 3 deaths were due to complications of alloSCT, 2 were due to sepsis (1 in the setting of refractory leukemia and 1 during MRD-negative CR), and 1 from unknown cause. Among 18 responding pts, only 1 pt relapsed; the pt with MRD-positive t(4;11) by FISH relapsed 4.5 months after alloSCT. The median OS for the R/R cohort was 5.8 months and was not reached for the frontline or MRD cohorts. The 1-year OS rate for the frontline + MRD cohort was 83%. Conclusion: Dose-dense mini-hyper-CVD in combination with InO and Blina achieves rapid MRD-negative remissions in patients with B-cell ALL. All responding patients achieved flow MRD negativity after 1 cycle of therapy, with the majority also achieving NGS MRD negativity. This regimen is now being prospectively evaluated in an ongoing clinical trial in pts with R/R B-cell ALL and in older adults with newly diagnosed B-cell ALL.

Treatment outcomes in adults with newly diagnosed B-cell acute lymphoblastic leukemia: A comparison between pediatric-inspired regimens and HyperCVAD at a Hispanic-serving cancer center.

7048 Background: It is unknown if HyperCVAD is more favorable than pediatric-inspired regimens (PIRs) among adult Hispanic patients with newly diagnosed B-cell acute lymphoblastic leukemia. This analysis aims to determine the interaction of Hispanic ethnicity and treatment regimen on outcomes. Methods: Records of adults (≥ 18 years) treated with a PIR or HyperCVAD from January 2011 to November 2022 at our institution were reviewed. Patients were excluded if they received treatment modifications in a clinical trial or were lost to follow-up prior to 6 months. The primary endpoint was event-free survival (EFS) comprised of relapse, death, secondary malignancy, or failure to achieve complete remission. Secondary endpoints included overall survival (OS). Ph+ disease was not grouped into the poor-risk category. Results: 100 patients were included. Median age was 39 years, 57% were male, and 61% self-identified as Hispanic. 48 were included in the PIR and 52 in the HyperCVAD groups. 37 in the PIR group received CALGB 10403. There was no difference in race, ethnicity, rituximab use, WBC, LDH, bone marrow blast %, presence of CNS disease at diagnosis, or poor-risk genetics (Table) between the PIR and HyperCVAD groups. However, a lower rate of Ph+ disease (8.3% vs 58%) and younger median age (31 years vs 49 years) was observed in the PIR group. Allogeneic stem cell transplantation (ASCT) was pursued in 48% of PIR and 37% of HyperCVAD-treated patients. EFS at 5-years was lower among patients receiving a PIR compared to HyperCVAD (28% vs 41%; hazard ratio [HR], 1.89; P = .022). After censoring for ASCT there was no change (P = .03). Treatment group was the only significant predictor for EFS although a treatment-by-subgroup interaction (P &lt; .10) with Hispanic ethnicity was found. OS at 5-years was 61% in PIR and 64% in HyperCVAD-treated patients (HR, 1.54; P = .25). In multivariable Cox regression analysis, Hispanic ethnicity (HR, 2.56; P = .041) and male sex (HR, 2.62; P = .027) were predictors for worse OS. Hispanic patients demonstrated worse EFS with a PIR compared to HyperCVAD (HR, 2.52; P = .008), which remained significant when evaluating only Ph- patients (HR, 2.20; P=.048). Non-Hispanics did not experience the same difference in EFS (HR, 0.88; P=.81). Conclusions: Treatment with a PIR resulted in worse EFS over HyperCVAD in adult Hispanic ALL patients. Future studies focusing on regimen intensity, adherence, and toxicities are needed to explore potential causes for this disparity. [Table: see text]

A phase II study of hyper-CVAD with blinatumomab (blina) and inotuzumab ozogamicin (INO) for newly diagnosed Philadelphia chromosome (Ph)–negative B-cell acute lymphoblastic leukemia (ALL).

e19017 Background: Consolidation with blina, regardless of measurable residual disease (MRD) status, improves overall survival (OS) in adults with newly diagnosed B-cell ALL. The addition of INO may deepen responses and further improve outcomes. Methods: Patients (pts) 14-59 years of age with newly diagnosed Ph-negative pre-B-cell ALL, including pts who had received no more than 1 prior cycle of chemotherapy, were eligible. Pts received hyper-CVAD alternating with high-dose MTX/Ara-C for up to 4 cycles, followed by 4 cycles of Blina at standard doses. Pts with CD20+ disease received 8 doses of an anti-CD20 antibody. Eight doses of prophylactic IT chemotherapy were given. Maintenance was with alternating blocks of POMP (maintenance cycles 1-3, 5-7, 9-11, and 13-15) and Blina (maintenance cycles 4, 8, and 12). Beginning with pt #39, INO at a dose of 0.3 mg/m2 on day 1 and 8 was added to the 2 cycles of MTX/Ara-C and to 2 cycles of Blina consolidation (4 total cycles with INO). Results: To date, 69 pts have been treated (38 without INO and 31 with INO). Baseline characteristics are summarized in the table. Among 53 pts with active disease at study entry, 100% achieved CR. MRD negativity by flow was achieved in 56/59 evaluable pts (95%). Of the 3 pts who did not achieve MRD negativity, 2 were later found to have a NUP214: ABL1 fusion, and 1 had KMT2A rearrangement. The median follow-up of the entire cohort is 26 months. Overall, 8 pts (12%) relapsed while on study, 22 (32%) underwent stem cell transplant (SCT) in first remission (2 of whom relapsed post-SCT), 2 (3%) died in CR, and 37 (54%) remain in continuous remission without SCT. For the entire cohort, the estimated 3-year OS was 87% and the 3-year continuous remission duration was 83%. With a median follow-up in the INO cohort of 15 months, 3 pts (10%) have relapsed, all with CNS-only relapses, and none has died. The 15-month OS in the cohorts with and without INO were 100% and 87%, respectively (P=0.06). One pt discontinued Blina due to recurrent grade 2 neurotoxicity. No pts have discontinued INO due to toxicity and no cases of SOS/VOD have been observed. Conclusions: In pts with newly diagnosed Ph-negative B-cell ALL receiving hyper-CVAD with sequential Blina, OS may be improved with the addition of INO. Clinical trial information: NCT02877303 . [Table: see text]

A Phase II Study of Mini-Hyper-CVD Plus Inotuzumab Ozogamicin, with or without Blinatumomab, in Older Adults with Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia: Updated Results and Predictors for Outcomes

Background: Inotuzumab ozogamicin (INO) and blinatumomab are superior to chemotherapy for relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). Incorporation of these agents in the frontline setting could improve remission durations and OS in older adults with newly diagnosed B-cell ALL. Methods: Patients (pts) ≥60 years of age with newly diagnosed Philadelphia chromosome (Ph)-negative pre-B-cell ALL were eligible. Pts were required to have a performance status of ≤3, total bilirubin ≤1.5 mg/dl, AST/ALT ≤3x ULN and creatinine ≤2 mg/dl. Pts received mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses) for up to 8 cycles. INO was given at a dose of 1.3-1.8mg/m2 on day 3 of cycle 1 and 0.8-1.3mg/m2 on day 3 of cycles 2-4. Rituximab (if CD20+) and prophylactic IT chemotherapy were given for the first 4 cycles. Responding pts received POMP maintenance for up to 3 years. To decrease the risk of veno-occlusive disease (VOD), the protocol was amended in 3/2017 (pts 50+) to give INO in fractionated doses each cycle (0.6 mg/m2 on day 2 and 0.3 mg/m2 on day 8 of cycle 1; 0.3 mg/m2 on day 2 and 8 of cycles 2-4) and to administer 4 cycles of blinatumomab following 4 cycles of hyper-CVD plus INO, followed by maintenance with 12 cycles of POMP and 4 cycles of blinatumomab (1 cycle of blinatumomab after every 3 cycles of POMP). The cumulative dose of INO given before and after this most recent amendment was 4.3 mg/m2 and 2.7 mg/m2, respectively. Results: To date, 80 pts have been treated. Six pts were in complete remission (CR) at the time of enrollment. Baseline characteristics are shown in Table 1. The median age was 68 years (range, 60-87 years); 30 pts (39%) were ≥70 years. From all pts, 39% were positive for TP53 mutation and 24% had an adverse-risk karyotype. Among 74 pts evaluable for morphologic response, 73 (99%) responded (CR, n=66; CRp, n=6; CRi, n=1). MRD negativity by flow cytometry was achieved in 61/76 pts (80%) after 1 cycle and 74/79 pts (94%) overall. The 30-day and 60-day mortality rates were 0% and 3%, respectively. Among 79 pts who achieved remission, 11 (14%) relapsed, 4 (5%) underwent allogeneic SCT in first remission (1 of whom subsequently relapsed), 32 (40%) are alive in remission without SCT, and 32 (40%) died in remission. Among the 32 deaths in remission, 9 were from sepsis, 3 from VOD, 9 from development of MDS or AML; the rest from miscellaneous causes. Overall, 9 pts (11%) developed MDS/AML after a median of 33 months (range 3-66); 7 of these pts had a detectable TP53 mutation in the myeloid malignancy. Notably, 6 pts (8%) developed VOD, 1 after subsequent allogeneic SCT. With a median follow-up of 61 months (range, 7-123 months), the 5-year CR and OS rates were 76% and 46%, respectively. Outcomes were superior in pts who were 60-69 years old versus those who were ≥70 years (5-year OS rates: 57% and 28%, respectively; P=0.05) and for those without poor-risk cytogenetics (e.g. KMT2A-rearranged, low hypodiploidy/near triploidy, complex cytogenetics) versus poor-risk cytogenetics (5-year OS rates: 55% and 21%, respectively; P=0.005). The 5-year OS for pts with and without TP53 mutation were 35% and 47%, respectively (P=0.34). The 5-year OS for pts age 60-64 was 65%, for those age 65-69 was 50%, and for those age ≥70 was 28%. The 3-year OS for patients with and without CRLF2+ ALL were 25% and 60%, respectively (P=0.12). Pts ≥70 years of age were more likely to die in remission (19/30 [63%]) and those who were 60-69 years of age (15/50 [30%]) (P=0.004), which was a major driver of the poor survival in this age group. Outcomes were favorable for pts age 60-69 years with poor risk cytogenetics (5-year OS 70%), intermediate for pts age 60-69 with poor risk cytogenetics (5-year OS 31%) or those age ≥70 with low risk cytogenetics (5-year OS 36%), and were very poor for pts age ≥70 with poor risk cytogenetics (5-year OS 0%) (Figure 1). Conclusion: Low-intensity chemotherapy with hyper-CVD plus INO, with or without blinatumomab, in older adults with newly diagnosed Ph-negative ALL resulted in very high rates of response (99%), including an MRD-negative response rate of 94%. This led to a 5-year OS rate of 46%. Despite the reduced intensity of this regimen, a substantial proportion of pts >70 years of age died in remission. Ongoing efforts are evaluated for INO and blinatumomab without chemotherapy for these pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Addition of Inotuzumab Ozogamicin to Hyper-CVAD Plus Blinatumomab Further Improves Outcomes in Patients with Newly Diagnosed B-Cell Acute Lymphoblastic Leukemia: Updated Results from a Phase II Study

The Addition of Inotuzumab Ozogamicin to Hyper-CVAD Plus Blinatumomab Further Improves Outcomes in Patients with Newly Diagnosed B-Cell Acute Lymphoblastic Leukemia: Updated Results from a Phase II Study

Prognostic significance of CNSL at diagnosis of childhood B-cell acute lymphoblastic leukemia: A report from the South China Children's Leukemia Group.

ObjectivesThe prognostic significance of acute lymphoblastic leukemia (ALL) patients with central nervous system leukemia (CNSL) at diagnosis is controversial. We aimed to determine the impact of CNSL at diagnosis on the clinical outcomes of childhood B-cell ALL in the South China Children’s Leukemia Group (SCCLG).MethodsA total of 1,872 childhood patients were recruited for the study between October 2016 and July 2021. The diagnosis of CNSL depends on primary cytological examination of cerebrospinal fluid, clinical manifestations, and imaging manifestations. Patients with CNSL at diagnosis received two additional courses of intrathecal triple injections during induction.ResultsThe frequency of CNLS at the diagnosis of B-cell ALL was 3.6%. Patients with CNSL at diagnosis had a significantly higher mean presenting leukocyte count (P = 0.002) and poorer treatment response (P <0.05) compared with non-CNSL patients. Moreover, CNSL status was associated with worse 3-year event-free survival (P = 0.030) and a higher risk of 3-year cumulative incidence of relapse (P = 0.008), while no impact was observed on 3-year overall survival (P = 0.837). Multivariate analysis revealed that CNSL status at diagnosis was an independent predictor with a higher cumulative incidence of relapse (hazard ratio = 2.809, P = 0.016).ConclusionCNSL status remains an adverse prognostic factor in childhood B-cell ALL, indicating that additional augmentation of CNS-directed therapy is warranted for patients with CNSL at diagnosis.

Impact of TKI combination therapy and MRD negativity on outcomes in Philadelphia chromosome-positive ALL: A retrospective, single-center experience.

e19052 Background: Presence of the Philadelphia chromosome (Ph+) in newly diagnosed B-cell acute lymphoblastic leukemia (ALL) conveys high-risk disease and a poor prognosis. Hematopoietic stem cell transplant (HSCT) following induction and achievement of remission remains the standard of care. In the era of TKIs targeting BCR-ABL1 in addition to newer combination strategies, the impact of HSCT in the first complete remission (CR) remains unclear, particularly in the context of measurable residual disease (MRD) negativity. We present the outcomes of Ph+ B-ALL patients with and without HSCT, stratified with respect to MRD negativity. Methods: We identified 32 patients with Ph+ B-cell ALL from January 2015 to January 2021 at our institution who were treated with TKIs and received HSCT with evaluable MRD prior to transplant. Baseline patient demographics were obtained, including labs, performance status at diagnosis, comorbidities, molecular profiling by NGS, doses of induction, toxicities, response, MRD analysis by PCR, HCT-CI scores, and HSCT outcomes. The event for calculating the overall survival (OS) was the date of death. Patients were otherwise censored at the date of last contact. Results: Of the 25 patients who underwent HSCT, the median age was 46 years and 48.0% were male. TKIs in combination with high-intensity regimens were given in 88.0% of patients at induction. There were no deaths within 60 days following induction. Twenty (80.0%) patients achieved CR or CRi, and of those, 56% were MRD-negative by the time of HSCT. At a median follow-up time of 4.74 years, the OS of patients that achieved CR following induction and HSCT was not reached, and there were no significant differences between the two groups (p = .1326). We then compared the 14 MRD-negative patients undergoing HSCT to 7 MRD-negative patients who did not undergo transplant aged ≤65 years with ECOG ≤2. There was no difference in age (p = .5353), ECOG score (p = .6364), or Charlson Comorbidity Index score (p = .7018) between the two groups. The median OS in the MRD-negative HSCT group was not reached and the median OS in the MRD-negative non-HSCT was 5.45 years (p = .0210). Conclusions: In the era of combination chemotherapy with TKIs, MRD positivity at the time of allogenic HSCT does not appear to impact survival at 5 years in this small retrospective cohort. Post-transplant TKI maintenance may abrogate MRD implications at the time of HSCT. Our findings demonstrate that Ph+ ALL patients benefit from HSCT when candidates, regardless of MRD status, as those undergoing HSCT demonstrated a statistically superior survival. HSCT appears to remain the standard of care despite newer combination strategies and MRD-driven treatment.

A phase II study of hyper-CVAD with sequential blinatumomab (Blina), with or without inotuzumab ozogamicin (INO), in adults with newly diagnosed B-cell acute lymphoblastic leukemia (ALL).

7034 Background: Blina and INO are highly effective in relapsed/refractory B-cell ALL and are associated with high rates of measurable residual disease (MRD) clearance. Use of these agents in the frontline setting may improve outcomes. Methods: Patients (pts) 14-59 years of age with newly diagnosed Philadelphia chromosome (Ph)-negative B-cell ALL, including pts who had received no more than 1 prior cycle of chemotherapy, were eligible. Pts received hyper-CVAD alternating with high-dose MTX/Ara-C for up to 4 cycles, followed by 4 cycles of Blina. Pts with CD20+ disease received 8 doses of an anti-CD20 antibody. Eight doses of IT chemotherapy were given. Maintenance was with alternating blocks of POMP (maintenance cycles 1-3, 5-7, 9-11, and 13-15) and Blina (maintenance cycles 4, 8, and 12). Beginning with pt #39, INO at a dose of 0.3 mg/m2 on day 1 and 8 was added to the 2 cycles of MTX/Ara-C and to 2 cycles of Blina (4 total cycles with INO). Results: Characteristics of the 58 treated pts (38 without INO and 20 with INO) are summarized in Table. Among 45 pts with active disease at study entry, 100% achieved CR. Overall, 76% achieved MRD negativity by flow cytometry after induction and 95% at any time over the course of therapy. The median follow-up of the entire cohort is 26 months (range, 3-61+ months). Overall, 5 pts (9%) relapsed, 18 (31%) underwent transplant in first remission (including an additional 2 pts who relapsed post-transplant), 2 (3%) died in CR, and 33 (57%) remain in continuous remission without transplant. All relapses occurred in pts with established poor-risk features and no relapses have occurred beyond 2 years. For the entire cohort, the estimated 3-year OS is 85% and the 3-year continuous remission duration is 84%. No relapses or deaths have occurred in the INO group, and the estimated 1-year OS is 100%. Treatment was overall well-tolerated. One patient discontinued Blina due to recurrent grade 2 neurotoxicity. No pts have discontinued INO due to toxicity and no cases of veno-occlusive disease have been observed. Conclusions: Hyper-CVAD with sequential Blina is highly effective as frontline treatment of Ph-negative B-cell ALL. The addition of INO to this regimen was safe and early results are encouraging, with no relapses observed to date. Clinical trial information: NCT01371630. [Table: see text]

Updated Results from a Phase II Study of Mini-Hyper-CVD Plus Inotuzumab Ozogamicin, with or without Blinatumomab, in Older Adults with Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia

Updated Results from a Phase II Study of Mini-Hyper-CVD Plus Inotuzumab Ozogamicin, with or without Blinatumomab, in Older Adults with Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia

27437 Disseminated Candida tropicalis in an immunocompromised pediatric patient

We report a case of a 12-year-old female with newly diagnosed B-cell acute lymphoblastic leukemia status post induction chemotherapy with hospital course complicated by Candida tropicalis fungemia requiring fluconazole. Two weeks after treatment initiation, she presented with a new onset fever and discrete erythematous papules, some with pseudovesicular appearance, along with erythematous macules and thin plaques localized to the upper extremities. At presentation, labs demonstrated pancytopenia, elevated beta-D-glucan assay (>500), and Candida tropicalis growth on both wound and tissue culture. Blood cultures were negative. Computed tomography with contrast demonstrated hypodense areas involving the liver, spleen, and pectoralis major muscle concerning for fungemic microabscesses. A right arm punch biopsy revealed a dense dermal inflammatory infiltrate consisting of numerous neutrophils, histiocytes, lymphocytes and eosinophils. Periodic acid Schiff diastase and Gomori methenamine silver stains highlighted many associated fungal organisms. A diagnosis of disseminated candida tropicalis was rendered. Treatment was changed from oral fluconazole to intravenous micafungin. Although her cutaneous involvement improved, she remained febrile. She was switched to amphotericin B and prednisone with marked improvement. This case highlights the difficulty in management of disseminated Candida tropicalis in immunosuppressed pediatric patients. The observed disseminated disease may be explained by emerging resistance of Candida tropicalis to fluconazole. Improvement of fever with prednisone supports the hypothesis that disseminated candidiasis causes an inflammatory response and emphasizes the importance of adjuvant corticosteroid therapy. Cutaneous involvement may indicate underlying disseminated disease, and dermatologists are crucial in the diagnosis and treatment of this opportunistic, often fatal disease.

Imbalance of Chemokines and Cytokines in the Bone Marrow Microenvironment of Children with B-Cell Acute Lymphoblastic Leukemia.

In the hematopoietic microenvironment, leukemic cells secrete factors that imbalanced chemokine and cytokine production. However, the network of soluble immunological molecules in the bone marrow microenvironment of acute lymphoblastic leukemia (ALL) remains underexplored. Herein, we evaluated the levels of the immunological molecules (CXCL8, CCL2, CXCL9, CCL5, CXCL10, IL-6, TNF, IFN-γ, IL-17A, IL-4, IL-10, and IL-2) in the bone marrow plasma of 47 recently diagnosed B-cell acute lymphoblastic leukemia (B-ALL) patients during induction therapy using cytometric beads arrays. The results demonstrated that B-ALL patients showed high levels of CXCL9, CXCL10, IL-6, and IL-10 at the time of diagnosis, while at the end of induction therapy, a decrease in the levels of these immunological molecules and an increase in CCL5, IFN-γ, and IL-17A levels were observed. These findings indicate that B-ALL patients have an imbalance in chemokines and cytokines in the bone marrow microenvironment that contributes to suppressing the immune response. This immune imbalance may be associated with the presence of leukemic cells since, at the end of the induction therapy, with the elimination and reduction to residual cells, the proinflammatory profile is reestablished, characterized by an increase in the cytokines of the Th1 and Th17 profiles.

Dehydropeptidase 1 Promoted Survival and Cell Cycle Progression through Regulation of CREB and P53 Pathways in B-Cell ALL

Background: Outcome of adults with B-cell acute lymphoblastic leukemia (ALL) remains poor and relapse is the major cause of treatment-failure. Identifying new biomarkers in B-cell ALL and studying their clinical significance and biological function will be helpful for risk-stratification, treatment decision and targeted therapy. Dehydropeptidase 1 (DPEP1) is a zinc-dependent metalloproteinase that is expressed aberrantly in several cancers. The role of DPEP1 in cancer remains controversial. In our previously conducted microarray analysis, DPEP1 was identified as one of most differentially expressed genes which were up-regulated in B-cell ALL more than 20-fold compared with normal bone marrow. However, the expression and biological function of DPEP1 in B-cell ALL remains unknown.Aims: To investigate the expression levels of DPEP1 in adults with B-cell ALL and to explore the biological function of DPEP1 in the cell line derived from B-cell ALL.Methods: A real-time quantitative RT-PCR was used to examine DPEP1 expression in 11 malignant hematological disorders cell lines and bone marrow samples from 146 adult acute leukemia and 26 health donors. We constructed 2 B-cell lines: DPEP1 over-expressing (OE) and DPEP1 knocked-down (KD) BV173 cell line to study the biological role of DPEP1 in B-cell ALL. The cell proliferation and colony formation were detected by CCK-8 and colony formation assay. The cell apoptosis and cell cycle were analysed by flow cytometry. The cell migration ability was assayed by the transwell assay. Western blot was used to determine the protein level of signaling pathway.Results: These results showed that the relative levels of DPEP1 gene expression in marrow from the 126 newly diagnosed B-cell ALL(median 136%; range 0-1066%) were significantly higher than those of marrow from the 26 healthy donors(8.4%; 0-20.8%; p <0.01), whereas no significant difference was detected in newly diagnosed AML patients compared with health donors (Figure A). DPEP1 gene expression was higher in BV-173 cells derived from B-cell ALL, but nearly undetectable in cell lines derived from AML(KG-1, NB4, HL60, MEG-01), CML(K562), MM(MOLP2, SKO-007), lymphoma(U937, Raji, Ramos) and the normal B cell line IM-9. Proliferation was significantly decreased in DPEP1-KD cells compared with cells transfected with control lentivirus (OD value: 1.90±0.05 vs 1.68±0.06, p < 0.05). In contrast, DPEP1 over-expression markedly increased proliferation of transfected cells (OD value: 1.32±0.06 vs 1.72±0.03, p < 0.05) (Figure B). Silencing of DPEP1 expression significantly decreased numbers of colony-forming units compared with controls (65.7±10.4 vs 109.7±8.3, p <0.01), whereas DPEP1 over-expression had a converse effect (116.7±15.5 vs 106.7±6.6, p <0.05). Data from flow cytometry analyses showed DPEP1 expression promoted cell-cycle progression: DPEP1-OE BV173 had a higher percentage cells in S phases (43.19±0.35% vs 38.58±0.29%, p <0.01), whereas DPEP1-KD BV173 cells significantly prone to accumulate in G0/G1 phases compared with control cells (57.75±1.66% vs 50.78±0.39%, p <0.01) (Figure C). Migration and invasion activity were significantly enhanced in DPEP1-OE BV173 cells but attenuated in DPEP-KD BV173 cells as detected by transwell assay. However, DPEP1-KD significantly increased the apoptosis in BV173 cells (11.68±0.18% vs 1.72±0.12%, p <0.001) (Figure C). Then we sought to identify the pathway and molecular mechanisms that mediated the effect of DPEP1.The p-CREB were significantly up-regulated in DPEP1-OE cells but down-regulated in DPEP1-KD cells. And expression of p53 was increased in DPEP1-KD cells (Figure D).Conclusion: These findings suggest that abnormal expression of DPEP1 in leukemia may be involved in the pathomechanism of B-cell ALL. DPEP1 improves the proliferation, migration, invasion and promote the survival in B-cell ALL cells, which might be mediated via CREB and p53 pathways. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The Influence of Nutritional Status at Diagnosis of Childhood B-Cell Acute Lymphoblastic Leukemia on Survival Rates: Data from a Hispanic Cohort

The impact of nutritional status at diagnosis of childhood acute lymphoblastic leukemia (ALL) on survival rates was assessed in a Hispanic cohort. Children <16 years with newly diagnosed ALL-B from 2011 to 2019 were studied. Overweight and obesity were classified by body mass index (BMI) and Z-score according to WHO and CDC criteria. BMI, weight percentiles for age and Z-Score were assessed using the WHO Anthro (0-5 years) and AnthroPlus (5-19 years) programs. Cox model was used to estimate risk factors for relapse and death; differences between groups were assessed with Student’s T test for parametric and Mann-Whitney U test for non-parametric variables. Disease-free survival (DFS) and overall survival (OS) were determined by the Kaplan-Meier method, calculating time, status, cumulative survival and standard error with a 95% confidence interval. Equal data distribution was estimated with the log-rank test. One-hundred and seventy-two B-ALL children were studied. The overweight-obese group had a non-significant lower DFS (CDC: 54% vs. 60%, p = 0.80; WHO: 57% vs. 64%, p = 0.89) and OS rate (CDC:76% vs. 82%, p = 0.38; WHO:65% vs. 81%, p = 0.13). An association between nutritional status determined by CDC and WHO criteria at diagnosis of B-cell ALL and survival rates was not documented.

Hypercalcemia and Lytic Bone Lesions As a Rare Presentation of Acute Lymphoblastic Leukemia: A Case Report

Acute Lymphoblastic Leukemia (ALL) is a type of leukemia that generates from white blood cells in the bone marrow. ALL could present with different nonspecific symptoms. Hypercalcemia is a rare presentation in B-cell ALL. We reported a middle-aged man presented with hypercalcemia and osteolytic bone lesions without bone pain and a definitive diagnosis of B-cell ALL.