Chromosome-negative Acute Lymphoblastic Leukemia Research Articles

Linkage of cell division cycle 42 with clinical features, treatment response and survival in adult Philadelphia chromosome negative acute lymphoblastic leukemia

Cell division cycle 42 (CDC42) regulates the progression of leukemia via mediating proliferation and immune evasion of malignant cells. The study aimed to investigate the correlation of CDC42 with clinical features, treatment response, event-free survival (EFS) and overall survival (OS) in adult Philadelphia chromosome negative acute lymphoblastic leukemia (Ph− ALL) patients. CDC42 expression in bone marrow mononuclear cells was detected in 78 adult Ph− ALL patients and 10 donors using real-time reverse transcriptase-polymerase chain reaction. CDC42 was increased in adult Ph− ALL patients compared with donors (p < .001). Besides, elevated CDC42 was linked with pro-B ALL or early-T ALL (p = .038) and white blood cell (WBC) elevation at diagnosis (p = .025). Fifty (64.1%) and 23 (29.5%) patients had complete remission (CR) at 1 month and minimal residual disease (MRD) after CR, respectively. CDC42 was inversely associated with CR at 1 month (p = .034), but not MRD after CR (p = .066). Concerning survival, patients with CDC42 ≥ 3.310 (cut by median value in patients) showed a shortened EFS (p = .006) and OS (p = .036) compared to those with CDC42 < 3.310. In detail, patients with CDC42 ≥ 3.310 and CDC42 < 3.310 had 5-year EFS rate of 29.9% and 45.4%, and 5-year OS rate of 39.4% and 63.6%, correspondingly. Further multivariate Cox’s regression analyses revealed that CDC42 ≥ 3.310 was independently related to shorter EFS (hazard ratio = 2.933, p = .005). Elevated CDC42 is related with pro-B ALL or early-T ALL, WBC elevation at diagnosis, unfavorable treatment response and worse survival in adult Ph− ALL patients.

Percutaneous Perirenal Mass Biopsy in a Sitting Position Revealed Extramedullary Relapse of Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is a blood malignancy characterized by a rapid proliferation of lymphoid progenitor cells. Extramedullary relapse (EMR) is the recurrence of leukemia that occurs outside the bone marrow. The central nervous system is the most prevalent site of EMR in ALL, whereas other organs, particularly the renal organs, are less commonly involved. A 49-year-old man diagnosed with Philadelphia chromosome-negative ALL (Ph-negative ALL) received a second umbilical cord blood transplant (uCBT) and was confirmed to be in his third hematological complete remission. However, the perirenal mass lesion emerged after two weeks, and was difficult to detect on echography in the prone position. We successfully performed a percutaneous biopsy of the mass in a sitting position and pathologically identified it as EMR. After the diagnosis, chemotherapy was restarted, and the patient was scheduled to receive a third uCBT. This is the first report of EMR in a perirenal lesion of ALL and shows that this novel biopsy can be performed as a renal biopsy, even in a sitting position. This case is the first to describe a biopsy technique in detail and demonstrates the value of collaboration between hematologists and nephrologists in diagnosing EMR of the kidneys.

Inotuzumab Ozogamicin + Blinatumumab +/- Rituximab + Mini-Hcvd Shows Improved Tolerability with Similar Efficacy Compared to E1910 in Treatment of Philadelphia Chromosome Negative Acute Lymphoblastic Leukemia in Older Adults

CONCLUSION Philadelphia chromosome negative acute lymphoblastic leukemia (Ph- ALL) boasts contradicting survival rates given its binodal age distribution. While children and adolescents post 5-year overall survival (OS) rates of 89%, the stark contrast of 5-year OS of 20.4% in older adults greater than 65 years, makes this a challenging population to treat. Currently, there is no standard of care for the treatment of ALL with various regimens utilized dependent on age, co-morbidities, performance status, as well as physician/institute preference. One regimen that is commonly used is a combination of targeted therapies along with reduced intensity chemotherapy (inotuzumab ozogamicin, rituximab (if CD20+), blinatumomab and mini hyper fractionated cyclophosphamide, vincristine, and dexamethasone [Mini-HCVD]), which has demonstrated both improvements in survival while reducing treatment related toxicity. Another commonly accepted approach is a modified Berlin-Frankfurt-Munster (BFM) backbone (i.e., E1910). Despite the available options, there is a lack of comparison of these regimens. To answer this unanswered question, we compared the characteristics, outcomes, and toxicities of older adults with ALL treated with either Mini-HCVD or E1910 at our academic medical center. Medical records were retrospectively reviewed at Roswell Park Comprehensive Cancer Center to identify patients diagnosed with Ph- ALL treated with Mini-HCVD or E1910 between January 1 2016 - May 31 2022. Those with relapsed/refractory ALL or received E1910 in the setting of a clinical trial were excluded from the study. Demographics, disease-specific variables, and overall outcomes were collected in accordance with the institutional review board approved protocol. Primary outcome was 3-year overall survival rate, while secondary outcomes included best response in first 3 months, minimal residual disease (MRD) status at 3 months, 30-day mortality, as well as the frequency and incidence of toxicities per cycle. Best response was defined as less than 5% blasts on bone marrow biopsy with complete (CR) or incomplete (CRi) absolute neutrophil or platelet count recovery. MRD status was assessed via flow cytometry and next generation sequencing using ClonoSEQ®. Adverse events and their severity were characterized according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Differences in OS between two groups were examined by log-rank test. Propensity scores were obtained based on the baseline variables that with potentially imbalanced distributions (p&amp;lt;0.1). MRD status and response to treatment were compared using Fisher's exact test. Toxicities were summarized as frequencies for each treatment cycle. The incidence of grade 3-4 toxicities was defined as the number occurrence per treatment cycle and were compared using Poisson regression. 27 patients were included, with 15 (55.5%) receiving Mini-HCVD and 12 (44.5%) receiving E1910. Median age was 70 years (49-83), in Mini-HCVD arm and 63 years (47-74), in E1910 arm. Three-year OS was 61.9% for those who received Mini-HCVD (95% CI 40.2-95.3) and 28.1% for those who received E1910 (95% CI 10.9-72.9; p=0.23). In Mini-HCVD 77% and 69% of patients achieved CR/CRi and MRD negative status in the first three months, compared to 60% and 70% in E1910. Only 13% of patients in Mini-HCVD proceeded to transplant or CAR-T, compared to 58% in E1910 (p=0.0198). The most common treatment-related adverse events in both arms were cytopenias. Febrile neutropenia occurred in 47% of Mini-HCVD patients compared to 83% in E1910. There was no difference in rates of infections between arms. Mean incidence of grade 3/4 toxicity per cycle was 0.85/0.96 with Mini-HCVD and 1.03/1.65 with E1910 (p=0.0098). This retrospective single institute study demonstrates that the clinical outcomes of Mini-HCVD plus immunotherapeutic agents in older adults with Ph- ALL are similar to modified BFM backbone with reduced incidence of toxicity. While limited by small numbers, these results suggest that reduced intensity chemotherapy in combination with novel targeted agents could represent a new standard of care regimen in this historically difficult to treat patient population.

Age-Adapted Chemotherapy for Adults >40 Years Old with Philadelphia Chromosome Negative Acute Lymphoblastic Leukemia: Single Center Outcomes

Introduction: While pediatric-inspired regimens are preferred in younger adults with Ph-negative ALL, the optimal approach for treating adults age &amp;gt;40 with Ph-negative ALL has not yet been defined. In the U.S., hyperCVAD-based regimens are commonly used in this age group; however, hyperCVAD may be less effective than pediatric-inspired regimens in patients who are appropriate candidates for intensive therapy, and may be excessively toxic in patients who are poor candidates for intensive therapy. We explored giving two different multiagent chemotherapy regimens to adults age &amp;gt;40 with newly diagnosed Ph-negative ALL, depending on the individual patient's age and fitness level. Methods: At our institution starting in September 2020, patients between 40-60yo with good performance status received an intensive pediatric-inspired regimen based on the CALGB 10403 backbone, while patients &amp;gt;60yo (or 50-60 with poor PS) received a moderate-intensity multiagent chemotherapy backbone consisting of 2-part induction (induction-1: infusional doxorubicin/vincristine D1-4 + dexamethasone 40mg D1-4, 9-12, 17-20; induction-2: same as induction-1 plus cyclophosphamide 1000mg/m 2 on day 1) and consolidation with 6 cycles of chemotherapy, alternating between methotrexate (1g/m 2) plus peg-asparaginase (1,000U/m 2), and cytarabine (1g/m 2 x 6 doses). Prior to September 2020, patients in this age group received the hyperCVAD backbone. In both cohorts, patients not proceeding to allogeneic SCT in CR1 received POMP maintenance for up to 2 years. We reviewed charts of patients aged &amp;gt;40 with newly diagnosed Ph-negative ALL at University of Colorado Hospital from 2014-2023 to compare outcomes between patients treated before 09/2020 (“hyperCVAD” cohort) and after 09/2020 (“age-adapted” cohort). Results: Between 09/2020-04/2023, 17 adults with median age of 57 (range 40-81) with newly diagnosed Ph-negative ALL began treatment at our institution. 6 patients (age 40-56) received a modified pediatric-inspired regimen, and 11 patients (age 54-81) received a moderate-intensity regimen. 4 patients underwent allogeneic SCT in CR1 (including 1 for tMDS that developed during maintenance therapy). 3 patients received blinatumomab in CR1, 2 of whom subsequently received allo SCT. With a median follow-up of 16 months (range: 1-32 months), 1 patient relapsed during maintenance and 2 patients died from treatment-related mortality (1 during induction chemotherapy, 1 during salvage therapy for primary refractory disease). All three events occurred in patients who received the moderate-intensity regimen. Grade 3 or 4 asparaginase-related toxicities occurred in 2 patients (1 gr3 hyperbilirubinemia, 1 gr3 pancreatitis) and both resolved with supportive care. Between 2014-2020, 18 adults with median age of 58 (range 42-80) received hyperCVAD for newly diagnosed Ph- ALL. 6 patients received allogeneic SCT in CR1, and no patients received blinatumomab in CR1. With a median follow-up of 31 months (range: 7-94 months), 7 patients relapsed during consolidation or maintenance therapy and 3 relapsed after SCT. Among 10 patients who died during follow-up, 7 deaths were due to relapsed/refractory disease and 3 were due to treatment-related mortality (all 3 TRM were post-transplant). An improvement in relapse-free survival is seen in the cohort treated with age-adapted chemotherapy vs. the hyperCVAD cohort (p=0.045, log-rank test) (Figure 1), while there was no difference in overall survival (p=0.29) (not shown). Conclusions: Age-adapted multiagent chemotherapy is safe and effective in adults age &amp;gt;40 with Ph-negative ALL and may result in better outcomes than hyperCVAD. This is possibly due to better efficacy of pediatric-inspired chemotherapy for younger (40-60yo) patients and better tolerability of moderate-intensity chemotherapy for older (&amp;gt;60yo) patients, compared to hyperCVAD. Broad use of asparaginase in both the pediatric-inspired and moderate-intensity regimens may have also contributed to better outcomes in comparison to hyperCVAD. Incorporation of novel therapies in the frontline setting holds much promise to improve outcomes for older adults with Ph- ALL. Our observations suggest that the specific multi-agent chemotherapy regimen used, and in particular the incorporation of peg-asparaginase, may also affect outcomes significantly.

Venetoclax in Combination with Pediatric-Inspired Chemotherapy in Adults with Newly Diagnosed Acute Lymphoblastic Leukemia: Results of a Phase I Trial

Introduction: Young adults with acute lymphoblastic leukemia (ALL) have favorable outcomes compared with historical standards when treated with an asparaginase-containing pediatric regimen (Stock et al., Blood 2019). We have demonstrated the safety and efficacy of pediatric inspired chemotherapy (PIC) for adults up to age 60 (MSK protocol 12-266, Geyer et al., Haematologica 2021). However, cure rates for adults with ALL remain below 60%, prompting the need for novel agents. Venetoclax (ven) is a BCL2 inhibitor being tested in several clinical trials for ALL. Here, we present the first report of ven used in combination with a multiagent, asparaginase-containing chemotherapy regimen for the upfront treatment of ALL. Methods: We conducted a Phase I, single-center, single-arm clinical trial (NCT05386576) to evaluate the safety and efficacy of ven in combination with PIC in adults with newly diagnosed ALL. Adults aged ≤60 years diagnosed with Philadelphia chromosome negative ALL were eligible for the study. The primary objective was to evaluate the safety of ven in combination with asparaginase-based PIC and identify the maximum tolerated dose and recommended phase II dose. The secondary objectives were to assess the rate of complete remission (CR) and measurable residual disease (MRD) negative CR at day 15 and 28 of Induction I, and end of Induction II. The regimen consisted of 6 treatment phases as previously published (12-266). Ven was administered at a final dose of 400mg (with a rapid dose escalation from 100mg over 3 days) during Induction I (days 5-7 dose escalation, days 7-28 full dose), Induction II (days 1-14 and 29-42), Intensification I &amp; II (days 1-22), and Re-Induction I &amp; II (days 1-14 and 29-42). Measurable residual disease (MRD) was assessed by multiparameter flow cytometry with 10 -4 sensitivity. We used historical data from 22 patients (pts) treated on our previous study, who received the same chemotherapy backbone without ven, as a comparator. Median follow up was calculated using the reverse Kaplan Meier indicator. Duration of treatment was compared using the Wilcoxon rank-sum test. Proportions of pts who achieved MRD-CR were compared with the chi squared test. Results: At the time of analysis, 8 pts had enrolled in the study; all 8 pts completed induction I and 6 (75%) pts had completed induction II (Table 1). Median follow up was 171 days. The median age was 38.5 years (min 25, max 60). 50% of pts had B-cell ALL, and 50% T-cell (including 1 patient with early T-cell progenitor). One patient (12.5%) had CNS disease (CNS 3) at diagnosis. Four (50%) pts had intermediate risk cytogenetics by CALGB 19802 classification (Stock et al., Cancer 2013), 2 (25%) had unfavorable, and 1 (12.5%) favorable. Two (40% of B-ALL) had a Philadelphia-like phenotype. During Induction I &amp; II, 4 (50%) pts experienced febrile neutropenia, 6 (75%) grade 4 thrombocytopenia, and all 8 (100%) grade 4 neutropenia. No dose limiting toxicities, as defined per protocol, were observed. The average duration of Induction I on study was 46.6 days compared to 43.6 on 12-266 (p = 0.11). The average duration of Induction II on study for pts who had completed it at the time of analysis was 102 days compared to 74 days on 12-266 (p = 0.02), primarily due to cytopenias. Three (37.5%) of pts achieved an MRD negative CR by the end of Induction I. Of the 6 pts who had completed Induction II by time of analysis, 5 (83%) had achieved an MRD- CR, compared to 81% on 12-266 (p = 0.90) and 1 patient had refractory extramedullary disease. We assessed kinetics and depth of response by plotting the average blast percentage in the bone marrow by flow cytometry across three different timepoints. Pts on the study had numerically lower blast percentages at day 15, end of Induction I and end of Induction II compared to 12-266 (Figure 1). At the time of this analysis, no patient who entered CR had experienced disease relapse. Conclusions: Ven addition to a PIC backbone was overall safe with high MRD negative remission rates in this preliminary report. Compared to historical controls, pts treated with ven had a longer duration of Induction II primarily due to cytopenias, and we are amending the study to shorten ven duration during induction II. Pts treated with ven had a numerically faster reduction in bone marrow blasts compared to historical controls. Longer follow up in a larger patient population in this ongoing study will be required to assess long term toxicity and efficacy of this regimen.

Patterns of Care Among Adolescents and Young Adults Treated for Acute Lymphoblastic Leukemia: A Retrospective Study across Diverse US Practices

Background. Studies have demonstrated superior outcomes in adolescents and young adults (AYAs, age 15-39 years) with T-cell and B-cell/Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL) who are treated using pediatric-inspired regimens (PIRs). However, some AYAs continue to be treated with non-PIR or adult regimens (ARs) that are associated with less favorable outcomes. The extent to which hospitals and physicians in the United States (US) have adopted PIRs to treat ALL in AYA patients is not known. Additionally, limited knowledge exists about factors associated with use of AR. The objective of this study was to describe patterns of care in AYAs with newly diagnosed ALL, and identify patient, physician and hospital-level characteristics associated with use of PIRs vs. ARs in these patients. Methods. This retrospective study analyzed data collected from medical charts of AYAs with ALL across varied cancer care settings in the US. Patients were identified by treating oncologists, who were board certified in the relevant specialty and had 3-40 years of post-residency practice experience. Physicians were not eligible to participate if they were associated with a pharmaceutical company or a healthcare/government agency in paid capacity. Patients were included based on the following criteria: newly diagnosed with ALL, 15-39 years at diagnosis, and treated with frontline PIR or AR between January 2016 and April 2022. Patients with a prior history of cancer were excluded. Standardized data collection forms were used by participating physicians to collect patient and clinical characteristics, treatment patterns, and site characteristics. Physicians were compensated for participation for each completed chart. Descriptive statistics (mean, standard deviation [SD], frequency, percentages) were used to describe these characteristics. Chi-square and multivariate logistic regression analyses were conducted to evaluate potential associations of these variables with AR use. The study received IRB (Advarra, Inc.; IRB#: 00000971) exempt status. Results. The analytic sample consisted of 378 eligible patients. Patients were treated by 178 physicians, of which 16.8% were pediatric oncologists, 59.3% were adult oncologists, and 23.9% treated patients of all ages. The majority of patients were treated at adult centers (82 [21.1%]) or centers that treat patients of all age groups (279 [71.7%]); 24 patients (6.2%) were treated at pediatric centers. Approximately three-quarters (73.8%) were treated at academic centers and one quarter (26.2%) at community centers. Of the 378 patients, 230 (61%) patients were treated with a PIR and 148 (39%) with an AR. The proportions were similar for both B-cell/Ph- patients (71.3% and 28.3%, respectively) and T-cell phenotypes (46.5% and 53.4%, respectively). Children's Oncology Group (COG)-based protocols were the most common PIR used (60.4%) followed by CALGB 10403 (23%). Among those receiving ARs, HyperCVAD-based regimens was most commonly used (n=125 [84.7%]). Of patients receiving HyperCVAD, 85.6% did not receive any immunotherapy. In univariate analyses, the use of an AR was significantly higher in subgroups of older AYAs (20-39y), males, and patients with public insurance. AYAs who were obese, had CNS involvement at diagnosis, T-cell immunophenotype, Ph+, Ph-like, or early T-cell precursor (ETP) were associated with AR use. Patients treated at non-pediatric centers, small-medium size hospitals (&amp;lt;500 beds), or those treated by non-pediatric oncologists (those who treat adult only or both adult and pediatric patients) were more likely to receive AR (Table 1). In multivariate analysis, patient factors independently associated with use of an AR included older age, obesity, Ph+, and Ph-like. Patients treated at small/medium size hospitals or non-pediatric centers were also significantly more likely to receive an AR vs. PIR (Table 2). Conclusions. The study provides “real-world” insights into treatment approaches used for AYAs with ALL across diverse cancer care settings. Nearly one-half of AYAs with T-cell ALL and one-third of AYAs with B-cell/Ph- ALL received AR. Additional studies are needed to understand the reasons behind the limited uptake of PIR, especially among older AYAs and in smaller and adult treatment settings.

Liver failure after treatment with inotuzumab and polychemotherapy including PEG-asparaginase in a patient with relapsed Philadelphia chromosome–negative acute lymphoblastic leukemia

We present the case of a 58-year-old female patient who presented with an extramedullary B-ALL relapse after prior allogenic HSCT and blinatumomab therapy. The patient died from complications of a drug-induced acute liver failure after a salvage therapy combining inotuzumab ozogamicin (InO)-based induction followed by consolidation with high dose MTX and pegaspargase based on the GMALL protocol for older ALL patients. After a diagnosis of the extramedullary relapse in the form of a retro vesical chloroma, the patient received an individualized multi-agent chemotherapy based on induction chemotherapy for older patients in combination with InO. After four administrations of InO, in combination with vincristine, dexamethasone, cytarabine, and cyclophosphamide, CT-imaging showed a reduction in volume of the chloroma and response to therapy. Consolidation with high-dose methotrexate and pegaspargase was administered. The patient developed toxic liver damage manifested by hyperbilirubinemia and progressive hepatic encephalopathy. The diagnostic criteria for VOD were met, and therapy with defibrotide was initiated. Liver biopsy revealed no histological signs of VOD but instead steatohepatitis indicative of drug-induced toxicity. The patient ultimately died of hemorrhagic shock through postinterventional hemorrhage after liver biopsy. In conclusion, although InO shows promising results in the therapy of r/r ALL with and without additional chemotherapy, the combination with MTX and pegaspargase in an intensively pretreated patient with relapse after HCST may impart an increased risk for liver-related toxicity. Special caution is required when assessing fitness for further liver toxic regimens. A key takeaway is also the reminder that InO can cause liver damage not only in the form of VOD but also through direct hepatocellular toxicity.

Location-based cancer survival in Philadelphia chromosome-negative acute lymphoblastic leukemia: An urban center retrospective analysis.

e18679 Background: Acute lymphoblastic leukemia (ALL) is an aggressive hematological malignancy requiring frequent transfusion support, receipt of multiagent chemotherapy, and for many patients, an allogeneic stem cell transplant. Social determinants of health impact access to care and overall survival in many cancers. However, findings by specific cancer types are inconsistent and vary widely. This study aimed to investigate the impact of location of residence and overall survival in Philadelphia chromosome-negative (Ph-) ALL in an underserved urban setting. Methods: We analyzed 112 patients with Ph- ALL at VCU Massey Cancer Center between 2010 and 2021 in a single-center, retrospective analysis. Sixteen patients did not have location data available. We stratified the remaining 96 patients into two cohorts based on travel distance from the patient's zip code to our center (greater than or less than 50 miles). We stratified patients based on urban or rural habitation using the Rural-Urban Commuting Area Codes (RUCA) classification system. Finally, we stratified patients by the region of Virginia from which the patients were traveling, creating four cohorts: Southside, Northern, Hampton Roads, and Eastern VA. We collected baseline demographics, performance status, disease characteristics, receipt of allogeneic stem cell transplant, and survival. We analyzed survival by the Kaplan-Meier method and compared groups with the Mantel-Cox test. The date of death was used to calculate overall survival; patients were censored at the date of the last contact. Results: Eleven patients (11%) living in rural areas were identified based on RUCA classification; 85 (81%) lived in an urban setting. Overall survival nonsignificantly favored the urban cohort (12.1 y. versus 3.8 y. in the rural cohort, p = 0.873). We combined 51 patients in urban and rural areas outside of Richmond into a single cohort and compared the survival of 45 patients from Richmond — the median survival in Richmond was not reached at a median follow-up time of 4.1 y. Comparatively, the median overall survival of areas outside of Richmond were as follows: 3.3 y. for Southside VA, 5.9 y. for Eastern VA, 12.1 y. for Northern VA, and not reached for Hampton Roads; there were no significant differences between these groups ( p = 0.131). The median overall survival was significantly worse for patients further than 50 miles from VCU compared to within 50 miles of VCU (6.5 years versus not reached at a median follow-up time of 4.2 y., p = 0.042). Conclusions: Areas surrounding Richmond, VA are medically underserved; those with aggressive malignancies — such as ALL — have an increased risk of toxicities with complicated treatment regimens. Indeed, our data demonstrate a survival benefit merely from living close to our center. These results may be influenced by socioeconomic factors impacting access to care.

Pediatric chemotherapy versus allo-HSCT for adolescent and adult Philadelphia chromosome-negative ALL in first complete remission: a meta-analysis.

Pediatric-inspired chemotherapy significantly improves survival for adolescent and adult patients with acute lymphoblastic leukemia (ALL). However, the benefits over allogeneic hematopoietic stem cell transplantation (allo-HSCT) remain unclear. To compare clinical outcomes between pediatric-inspired chemotherapy and allo-HSCT in consolidation therapy of adolescent and adult Philadelphia chromosome-negative (Ph-neg) ALL in first complete remission (CR1), related studies from MEDLINE, Embase, and Cochrane Controlled Register of Trials updated to July 2022 were searched. A total of 13 relevant trials including 3161 patients were included in the meta-analysis. Compared with allo-HSCT, pediatric-inspired chemotherapy achieved better OS (hazard risk (HR), 0.53; 95% confidence interval (CI), 0.41 to 0.68) and DFS (HR, 0.64; 95% CI, 0.48 to 0.86), with a significant reduction in NRM (risk ratio (RR), 0.30; 95% CI, 0.18 to 0.51), but no difference in the relapse rate (RR, 1.13; 95% CI, 0.93 to 1.39). When only studies based on intention-to-treat analysis were included, pediatric-inspired chemotherapy consistently conferred a survival advantage. In subgroup analyses, patients with baseline high-risk features demonstrated similar OS and DFS between pediatric-style chemotherapy and allo-HSCT, while pediatric-style chemotherapy had an OS and DFS advantage in standard-risk subgroup. Particularly, patients with positive minimal residual disease (MRD) achieved better OS and DFS if proceeded to allo-HSCT.

Approach to the Treatment of Philadelphia Chromosome-Negative B-cell ALL in Older Adults: Is Age Becoming just a Number?

Despite progress in the treatment of pediatric B-cell acute lymphoblastic leukemia (ALL) and PH + ALL, fewer advancements have been for older adults with PH-negative B-cell ALL. Treatment of this population is mired by higher incidence of poor risk biologic features, increased incidence of medical comorbidities, and higher rates of treatment-related mortality (TRM). Here, we review the difficulties in managing elderly patients with PH-negative ALL. The development of novel agents has brought additional tools to the armamentarium of drugs and has changed the landscape of treatment. More recent clinical trials and future clinical trials focus on blinatumomab, inotuzomab ozogamicin (IO), and/or chimeric antigen receptor T-cell (CAR-T) either alone or integrated with dose-reduced chemotherapy regimens. The introduction of novel agents/therapies and incorporation into our current treatment paradigms may finally offer an avenue to improve the dismal outcomes seen in this population.

Venous thromboembolism incidence associated with pegylated asparaginase (ASP) compared to the native L-ASP: A retrospective analysis with an ASP-based protocol in adult patients with acute lymphoblastic leukaemia.

Venous thromboembolism (VTE) is a well-known complication in patients with acute lymphoblastic leukaemia (ALL) receiving asparaginase (ASP)-based chemotherapy, including the ASP-intensive Dana-Farber Cancer Institute (DFCI) 91-01 protocol for adults. Since 2019, native L-ASP is no longer available in Canada and was replaced by pegylated (PEG)-ASP. To determine whether the incidence of VTE has changed since switching from L-ASP to PEG-ASP, we conducted a single-centred retrospective cohort study. We included 245 adult patients with Philadelphia chromosome negative ALL between 2011 and 2021, with 175 from the L-ASP group (2011-2019) and 70 from the PEG-ASP group (2018-2021). During Induction, 10.29% (18/175) of patients who received L-ASP developed VTE, whereas 28.57% (20/70) of patients who received PEG-ASP developed VTE (p= 0.0035; odds ratio [OR] 3.35, 95% confidence interval [CI] 1.51-7.39), after adjusting for line type, gender, history of VTE, platelets at diagnosis. Similarly, during Intensification, 13.64% (18/132) of patients had VTE on L-ASP while 34.37% (11/32) of patients on PEG-ASP developed VTE (p= 0.0096; OR 3.96, 95% CI 1.57-9.96 with multivariable analysis). We found that PEG-ASP is associated with a higher incidence of VTE compared to L-ASP, both during Induction and Intensification, despite the administration of prophylactic anticoagulation. Further VTE mitigation strategies are needed in particular for adult patients with ALL receiving PEG-ASP.

Improved Outcomes with Low-Dose Inotuzumab and Mini-Hyper-CVD Followed By Blinatumomab Consolidation in Relapsed-Refractory Acute Lymphoblastic Leukemia: Results of a Phase II Study

Background: Patients (pts) with relapsed-refractory (R-R) acute lymphoblastic leukemia (ALL) have a poor prognosis. The combination of low-intensity chemotherapy with mini-hyper-CVD (mini-HCVD) and inotuzumab has shown encouraging results. The aim of this study is to evaluate whether the sequential addition of blinatumomab to mini-HCVD-inotuzumab with lower doses of weekly inotuzumab might further improve outcomes. Methods: Pts with Philadelphia chromosome-negative B-cell ALL were included. Odd cycles of mini-HCVD consisted of cyclophosphamide (150 mg/m2 every 12 h on days 1-3), vincristine (2 mg flat dose on days 1 and 8), and dexamethasone (20 mg on days 1-4 and days 11-14) without anthracyclines. Even cycles consisted of cytarabine (0.5 g/m2 given every 12 h on days 2 and 3) and methotrexate (250 mg/m2 on day 1). During the first 4 courses, pts received rituximab when CD20 expression was ≥20%, and intrathecal chemotherapy. Initially, inotuzumab was administered on day 3 of the first 4 cycles at the dose of 1.3-1.8 mg/m2 in course 1, followed by 1.0-1.3 mg/m2 in subsequent courses. Pts received maintenance therapy with POMP, consisting of 1 year of monthly prednisone 50 mg/d for 5 days and vincristine at 2 mg every month, along with 3 years of 6-mercaptopurine 50 mg twice daily and weekly oral methotrexate 10 mg/m2. An amendment to the protocol was made after the inclusion of 67 pts to add 4 cycles of blinatumomab after 4 cycles of the combination mini-HCVD + inotuzumab. Inotuzumab was given on days 2 and 8 at the dose of 0.6 and 0.3 mg/m2 in course 1, respectively, followed by days 2 and 8 at the dose of 0.3 and 0.3 mg/m2 in subsequent courses; blinatumomab was continuously infused over 28 days every 42-day cycle for 4 cycles. Maintenance therapy was reduced to 12 courses of POMP with 1 course of blinatumomab after each 3 courses of POMP for a total of 4 courses. The decision to undergo allogeneic stem cell transplantation (ASCT) was based on the discretion of the treating physician after discussion with the patient. Results: Between February 2013 and July 2021, 112 pts were treated on study, including 45 pts with mini-HCVD + inotuzumab + blinatumomab. Baseline characteristics and outcomes are summarized in Table 1. The median follow-up is 41 months (range, 3-112). Before the study amendment, 67 pts were treated: 38 (57%) in salvage(S)1, and 29 (43%) in S2+. Nineteen pts (28%) had received prior ASCT. After the amendment, additional 45 pts were treated: 42 (93%) in S1, and 3 (7%) in S2+; 3 (7%) pts had prior ASCT. The overall response rate (ORR) was 83% (CR, 63%) in the entire cohort, 76% (CR, 60%) pre-amendment, and 93% (CR, 67%) post-amendment. Among 91 responders evaluable for measurable residual disease (MRD), 76 pts (82%) achieved MRD negativity by multicolor flow cytometry, with higher rates of MRD negativity in S1 (89%). The rates of MRD negativity before and after the amendment were 82% and 85%, respectively. Overall, 53 (47%) pts underwent ASCT: 29 (43%) pts pre-amendment and 24 (53%) post-amendment. The median overall survival (OS) for the entire cohort was 17 months, with a 3-year OS rate of 41%. After the amendment, the addition of blinatumomab resulted in superior median OS (37 months vs 14 months) and 3-year OS rates (55% versus 34%) (Figure 1). Pts in S1 had better survival compared with those in S2+, with 3-year OS of 51% and 17%, respectively (P=0.001). In a 2-month landmark analysis among pts in S1, the median OS was 57 months in those who received blinatumomab compared with 31 months in those who did not. Overall, pts who achieved MRD negativity had higher 3-year OS rate of 55% compared to 10% in pts who were MRD-positive at best response (P=0.0001). Survival with mini-HCVD + inotuzumab +/- blinatumomab compared favorably to that of inotuzumab monotherapy: 17 months vs 6 months; P<0.0001. A 3-month landmark analysis among responders showed similar 3-year OS rates between pts who underwent subsequent ASCT and those who did not (55% vs 48%, respectively). Veno-occlusive disease (VOD) was observed in 10 of the 112 pts (9%), and its incidence was reduced from 13% with single dose of inotuzumab to 2% with fractionated dose schedule (P=0.056). Conclusion: The addition of blinatumomab to mini-HCVD-inotuzumab, along with a lower weekly dose of inotuzumab, further improves the outcomes of pts with R-R ALL. These adjustments reduced the rate of VOD and improved survival. Long-term survival was similar regardless of subsequent ASCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Anlotinib exerts potent antileukemic activities in Ph chromosome negative and positive B-cell acute lymphoblastic leukemia via perturbation of PI3K/AKT/mTOR pathway

ObjectivesDespite advances in the development of novel targeted therapies, the need for B-ALL alternative treatments has not been met. Anlotinib could blunt the proangiogenic activity of VEGFR, PDGFR, and FGFR, and has shown strong antitumor activities across multiple tumors. However, anlotinib cytotoxicity against B-ALL has not ever been evaluated, thus prompting us to initiate this study. MethodsExpression2Kinases program was used to identify potential treatment targets. Cell viability and apoptosis were determined by CCK-8 and Annexin V/PI staining kit, respectively. qRT-PCR and Western blotting were utilized to investigate the molecular mechanisms. In vivo antileukemia activity of Anlotinib was evaluated in a Ph+ B-ALL patient-Derived Xenograft (PDX) model. ResultsCompared with treatment-naive B-ALL cases, RR B-ALL patients had higher activities in the VEGF/VEGFR signaling and the PI3K/AKT/mTOR pathway. Exposure of Ph− and Ph+ B-ALL cells to anlotinib resulted in significant cell viability reduction, apoptosis enhancement, and cell cycle arrest at G2/M phase. Importantly, anlotinib treatment led to remarkably decreased leukemia burdens and extended the survival period in a Ph+ B-ALL PDX model. Blockade of the role of the proangiogenic mediators, comprising VEGFR2, PDGFR-beta, and FGFR3, played a critical role in the cytotoxicity of anlotinib against Ph− and Ph+ B-ALL. Moreover, anlotinib dampened the activity of PI3K/AKT/mTOR pathway that resides in the convergence of the three mentioned proangiogenic signals. ConclusionThis work provides impressive preclinical evidence of anlotinib against Ph− and Ph+ B-ALL and raises a rationale for future clinical evaluation of this drug in the management of Ph− and Ph+ B-ALL.

Controversies in the Treatment of Adolescents and Young Adults with Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia.

The incidence of acute lymphoblastic leukemia (ALL) has been increasing steadily in the adolescent and young adult (AYA) population. In this review article focused on the management of AYAs with Philadelphia chromosome-negative (Ph-) B-ALL, we examine topics of clinical interest and identify areas of controversy in need of further investigation. We explore four areas of active investigation: pediatric-inspired front-line treatment regimens, the optimal time of measurable residual disease (MRD) assessment, the role of hematopoietic stem cell transplant and the optimal salvage therapy for relapsed/refractory B-ALL in AYAs. There has been rapid advancement in the management of ALL in the AYA patient population, which has resulted in improved outcomes. We must build on the successes by continuing to promote multi-center innovative clinical research with clinical trial populations reflecting the AYA ALL patient spectrum. The incorporation of novel targeted immunotherapy into front-line treatment will be transformative and redefine treatment paradigms in the coming years.

Long-Term Follow-up of the Combination of Low-Intensity Chemotherapy Plus Inotuzumab Ozogamicin with or without Blinatumomab in Patients with Relapsed-Refractory Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia

Long-Term Follow-up of the Combination of Low-Intensity Chemotherapy Plus Inotuzumab Ozogamicin with or without Blinatumomab in Patients with Relapsed-Refractory Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia

Dynamics of Measurable Disease at Remission Determines Survival in Patients (Pts) with Philadelphia Chromosome Negative B-Cell Acute Lymphoblastic Leukemia (ALL)

Dynamics of Measurable Disease at Remission Determines Survival in Patients (Pts) with Philadelphia Chromosome Negative B-Cell Acute Lymphoblastic Leukemia (ALL)

Economic Burden Associated with Adverse Events of Special Interest (AESI) in Patients with Relapsed Acute Lymphoblastic Leukemia (ALL) in the US

IntroductionAcute lymphoblastic leukemia (ALL) is a type of cancer in which body overproduces lymphoblasts in the bone marrow (National Cancer Institute, 2016). Relapsed Philadelphia chromosome-negative (Ph-) B-cell ALL patients are extremely ill, and further compromised by treatment; hence, complications due to either the disease or the treatment are very common and often managed with inpatient admission. Infections, cytopenia and gastrointestinal (GI) toxicity events are often mentioned as important adverse events of special interest (AESI) among ALL patients (Hummel et al., 2016; Offidani et al., 2004, Schmiegelow et al., 2017) with detrimental impact on patients' quality of life. However, the economic burden of these events is not well documented in the published literature.ObjectiveThe aim of this study is to quantify the rates and economic burden of infections, cytopenia, and GI toxicity events among adults with relapsed Ph- ALL in the US.MethodsThis was a retrospective cohort study using Truven Health MarketScan® Commercial and Medicare Supplemental Databases. Patients with ≥1 inpatient claims or ≥2 non-diagnostic outpatient claims at least 30 days apart for relapsed ALL diagnosis (ICD-9-CM 204.02, ICD-10-CM C91.02) during 4/1/2009 - 10/31/2016 were extracted. All patients were required to have ≥1 hospitalization with diagnosis-related group in 834-839 on or after the first relapsed ALL diagnosis (index date was the admission date for the first hospitalization), were ≥18 years old on index date, and had ≥6 months of continuous enrollment prior to index date. Patients with medications for Ph+ or T-Cell ALL anytime during the study period were excluded. Patients were followed until the earliest event of inpatient death, end of continuous enrollment, end of the study period (10/31/2016), or 100 days post-index. AESI was defined as infections (including bacteremia, febrile neutropenia, line infections, pneumonia and sepsis), cytopenia (including anemia, neutropenia, thrombocytopenia and other cytopenia), or GI toxicities (including nausea/vomiting, diarrhea, gastritis/duodenitis, GI bleeding and mucositis/stomatitis) during the follow-up period. Outcomes included proportion of patients with AESI and AESI-related healthcare costs for any AESI and specific AESI categories and events. The AESI-related costs were calculated among those with at least one AESI and were the total costs accumulated during the follow-up after index date at the patient level. Costs were sum of the plan paid amount and out-of-pocket amount in 2016 US dollars.ResultsA total of 400 relapsed Ph- ALL patients were identified and 92.5% of them (mean age: 41.9 years; male: 63.0%; mean Charlson comorbidity index: 3.0) experienced at least one AESI during a mean (median) follow-up period of 84 (100) days. Among all the relapsed Ph- ALL patients with AESI, 64.6% had infections, 94.6% had cytopenia, and 46.2% had GI toxicity events (Table 1). The most frequent infection event observed was sepsis (40.0%); the most frequent cytopenia events were neutropenia (68.4%) and anemia (63.0%); and nausea/vomiting (26.8%) was the most frequent GI toxicity event. The total average (SD; median) AESI-related healthcare costs during 100 days post index date was $197,213 ($308,551; $105,731) (Table 1). Across all patients with AESI, the mean (SD) number of AESI-related hospitalizations was 2.0 (1.3), with a total mean (SD; median) length of stay of 32.2 (26.0; 27.0) days during the follow-up. Mean (SD; median) healthcare costs were highest for infection-related events ($164,461 [$347,083; $64,528]), followed by cytopenia ($125,210 [$165,141; $67,475]) and GI toxicity-related events ($11,652 [$40,231; $1,349]). At the specific event level, average healthcare costs were highest for sepsis ($204,151 [$412,572; $79,853]) and other cytopenia-related events ($98,900 [$143,961; $39,777]).ConclusionsInfections, cytopenia, and GI toxicity events affect the vast majority of relapsed Ph- ALL patients. The economic burden associated with AESI is substantial, with infections the most expensive AESI, followed by cytopenia and GI toxicity. One limitation of this study is that we couldn't separate the AESI due to treatment from those due to the disease itself. Nonetheless, new therapies that can improve the outcomes of the relapsed Ph- ALL patients while offering a favorable safety profile are needed. [Display omitted] DisclosuresZhang:Amgen Inc.: Employment, Equity Ownership. Romanov:Amgen, Inc.: Employment, Equity Ownership. Cong:Amgen Inc.: Employment, Equity Ownership.

Hyper-CVAD plus ofatumumab versus hyper-CVAD plus rituximab as frontline therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: A propensity score analysis.

The outcome of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone plus ofatumumab hyper-CVAD + ofatumumab (hyper-CVAD + ofatumumab) has not been compared with the outcome of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone plus ofatumumab hyper-CVAD plus rituximab (hyper-CVAD + Rituximab) in Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) in a randomized clinical trial. The authors compared the outcomes of 69 patients treated with hyper-CVAD + ofatumumab and 95 historical-control patients treated with hyper-CVAD + Rituximab. Historical-control patients were treated with hyper-CVAD + Rituximab if they had CD20 expression ≥ 20%. Ofatumumab (day 1 of course 1, 300 mg intravenously; subsequent doses, 2000 mg intravenously) was administered on days 1 and 11 of courses 1 and 3 and on days 1 and 8 of courses 2 and 4 for a total of 8 doses. A propensity score analysis with inverse probability of treatment weighting (IPTW) was performed to adjust for baseline covariates between groups. The median event-free survival with stem cell transplantation (SCT) censoring was 33 and 65 months with hyper-CVAD + Rituximab and hyper-CVAD + ofatumumab, respectively (crude P = .064; IPTW P = .054). The median overall survival with SCT censoring was 52 months and not reached, respectively (crude P = .087; IPTW P = .097). Hyper-CVAD + ofatumumab was associated with better outcomes than hyper-CVAD + Rituximab among patients with newly diagnosed Philadelphia chromosome-negative ALL.

MRD-Based Therapeutic Decisions in Genetically Defined Subsets of Adolescents and Young Adult Philadelphia-Negative ALL.

Simple SummaryIn acute lymphoblastic leukemia (ALL), once a complete remission is achieved following induction chemotherapy, the study of submicroscopic minimal residual disease (MRD) represents a highly sensitive tool to assess the efficacy of early chemotherapy courses and predict outcome. Because of the significant therapeutic progress occurred in adolescent and young adult (AYA) ALL, the importance of MRD in this peculiar age setting has grown considerably, to refine individual prognostic scores within different genetic subsets and support specific risk and MRD-oriented programs. The evidence coming from the most recent MRD-based studies and the new therapeutic directions for AYA ALL are critically reviewed according to ALL subset and risk category.In many clinical studies published over the past 20 years, adolescents and young adults (AYA) with Philadelphia chromosome negative acute lymphoblastic leukemia (Ph− ALL) were considered as a rather homogeneous clinico-prognostic group of patients suitable to receive intensive pediatric-like regimens with an improved outcome compared with the use of traditional adult ALL protocols. The AYA group was defined in most studies by an age range of 18–40 years, with some exceptions (up to 45 years). The experience collected in pediatric ALL with the study of post-induction minimal residual disease (MRD) was rapidly duplicated in AYA ALL, making MRD a widely accepted key factor for risk stratification and risk-oriented therapy with or without allogeneic stem cell transplantation and experimental new drugs for patients with MRD detectable after highly intensive chemotherapy. This combined strategy has resulted in long-term survival rates of AYA patients of 60–80%. The present review examines the evidence for MRD-guided therapies in AYA’s Ph− ALL, provides a critical appraisal of current treatment pitfalls and illustrates the ways of achieving further therapeutic improvement according to the massive knowledge recently generated in the field of ALL biology and MRD/risk/subset-specific therapy

Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia with kinase fusions in Taiwan

Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukaemia (ALL), a high-risk subtype characterised by genomic alterations that activate cytokine receptor and kinase signalling, is associated with inferior outcomes in most childhood ALL clinical trials. Half of the patients with Ph-like ALL have kinase rearrangements or fusions. We examined the frequency and spectrum of these fusions using a retrospective cohort of 212 newly diagnosed patients with childhood B-cell ALL. Samples without known chromosomal alterations were subject to multiplex reverse transcription polymerase chain reaction to identify known Ph-like kinase fusions. Immunoglobulin heavy chain locus (IGH) capture and kinase capture were applied to samples without known kinase fusions. We detected known kinase fusions in five of 212 patients, comprising EBF1-PDGFRB, ETV6-ABL1, ZC3HAV1-ABL2, EPOR-IGH, and CNTRL-ABL1. Two patients with P2RY8-CRLF2 were identified. Patients with non-Ph kinase fusions had inferior 5-year event-free survival and overall survival compared with patients with other common genetic alterations. The prevalence of non-Ph kinase fusions in our Taiwanese cohort was lower than that reported in Caucasian populations. Future clinical trials with tyrosine kinase inhibitors may be indicated in Taiwan because of the inferior outcomes for B-cell ALL with kinase fusions.