Philadelphia Chromosome-negative Acute Lymphoblastic Leukemia Research Articles

Allogeneic stem cell transplant with TBI-based myeloablative conditioning in adolescents and young adults with Philadelphia chromosome-negative ALL treated with pediatric protocols

To investigate the safety of total body irradiation-based myeloablative conditioning (TBI-MAC) in adolescent and young adult (AYA) Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) patients treated with pediatric protocols, treatment outcomes of 106 AYA patients aged 16–39 years old undergoing allogeneic stem cell transplant (allo-SCT) with TBI-MAC in the first remission were compared according to chemotherapy types before transplant. Pediatric and adult protocols were used in 56 and 50 of the patients, respectively. The cumulative incidence (CI) of non-relapse mortality (NRM) and the overall survival (OS) rates were not significantly different between the pediatric-protocol and adult-protocol group (NRM: 4 % vs. 14 % at five years post-transplant, respectively, p = 0.26; OS: 81 % vs. 66 %, respectively, p = 0.14). Multivariate analysis for NRM revealed that a performance status >0 (hazard ratio [HR] = 4.8) and transplant due to chemotherapy toxicities (HR = 3.5) were independent risk factors, but a pediatric protocol was not (HR = 0.48). The CI of NRM and the OS rates were also similar among patients aged over 24 years old. These findings suggested that conventional allo-SCT with TBI-MAC can be performed without increasing NRM in AYA patients with Ph-negative ALL even after pediatric protocols.

Outcomes and adverse events in older acute lymphoblastic Leukemia patients treated with a pediatric-inspired protocol with Pegylated or native Asparaginase

ABSTRACT This retrospective report presents the outcomes and adverse events (AEs) observed in 73 patients aged 60 years or older diagnosed with Philadelphia Chromosome-negative Acute Lymphoblastic Leukemia (Ph-negative ALL) treated with a pediatric-inspired protocol incorporating either Pegylated (PEG-ASP) or Native Asparaginase (EC-ASP). Notably, 61% of patients experienced AEs of Grade III-IV severity. The most prevalent AEs included thrombosis (35.6%), febrile neutropenia (38.4%), and transaminitis (34.2%). AEs did not translate into significant differences concerning overall survival, leukemia-free survival, or early mortality. Furthermore, we observed a reduction in early mortality rates (11% vs. 20%) and an increase in median overall survival (54 vs. 48 months) compared to our previous data. These findings suggest that the utilization of a pediatric-inspired chemotherapy protocol, with ASP, is an effective and well-tolerated therapeutic option for older patients with Ph-negative ALL. However, it emphasizes the importance of diligent monitoring and close follow-up throughout treatment.

A pediatric-inspired regimen for adolescent and adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia: a prospective study from China.

Several international centers have used and reported on pediatric-inspired regimens to treat adolescent and adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph- ALL). However, there is a lack of prospective data from the Chinese population. We performed a prospective study with a pediatric-inspired regimen (IH-2014 regimen) to treat adolescent and adult Ph- ALL patients in our center. From 2014 to 2021, a total of 415 patients aged between 14 and 65 years (median age, 27 years) were included in this study. After a median follow-up of 40.8 months, the 5-year overall survival, disease-free survival, and event-free survival rates were 53.8%, 51.1% and 45.0%, respectively. The regimen was generally well tolerated and safe, and the overall chemotherapy-related mortality was 3.6%. Age ≥40 years and persistent detectable minimal residual disease (MRD) after induction were independent prognostic factors. Traditional risk factors for adult patients combined with post-induction MRD had predictive significance for survival and relapse, which is helpful in the selection of subsequent treatment. Patients with high-risk factors who can achieve a deep MRD response after induction do not derive benefit from allogeneic hematopoietic stem cell transplantation.

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.

Prognostic Value of MRD By Flow Cytometry in Adolescent and Adult Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia Treated with Pediatric-Inspired Regimen: A Post-Hoc Analysis from a Prospective Study of China

Background Minimal residual disease (MRD) is currently considered as one of the most powerful predictors in patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph - ALL).The time points and thresholds for MRD monitoring in pediatric Ph - ALL have been well established. However, surveillance strategy in adult ALL has not yet been standardized. In this study, we explored the prognostic value of MRD levels and monitoring time points by flow cytometry (FCM) in adolescent and adult patients with Ph - ALL treated with pediatric-inspired regimen. Methods This analysis includes adolescent and adult patients who were treated according to a pediatric-inspired regimen revised based on Children's Oncology Group protocol (CCG-1961). This prospective study was registered at Chinese Clinical Trial Registry Website with the registration number of ChiCTR-OOC-15006328. MRD was measured using bone marrow aspirates with eight-color multiparametric FCM on day 14 of induction, at end of induction (EOI, days 29-42) , post the first consolidation (post-C1), and throughout the treatment period. MRD was defined as the percentage of lymphoblasts present in the total nucleated cells counted. MRD levels of < 0.01% and ≥ 0.01% was considered as negative and positive, respectively.Patients who were MRD-positive were further stratified into three groups according to MRD level: MRD low positive (MRD-lp), ≥ 0.01% to < 0.1%; MRD high positive (MRD-hp), ≥ 0.1% to < 1%; and MRD very high positive (MRD-vhp), ≥ 1%. Results From 2014 to 2021, a total of 415 patients with a median age of 27 (range: 14-69) years were treated. Three hundred and twelve patients presented with B-precursor ALL and 103 with T-cell ALL. With a median follow-up time of 40.8 months, the median overall survival (OS) of the cohort has not yet been reached. There were 386, 389, and 346 BM samples available for MRD evaluation on day 14 of induction, at EOI, and post-C1, respectively. Figure 1A presents the distribution of MRD status over time. Figure 1B depicts the compositions of MRD levels at EOI stratified according to disease types. Notably, Ph-like ALL and early T-cell precursor (ETP) ALL were associated with extremely lower achievements of MRD negativity at EOI compared with other types. The 5-year OS rates of patients with MRD negativity, MRD-lp, MRD-hp, and MRD-vhp at EOI were 68.0% (95% CI: 60.2%-75.8%), 44.8% (95% CI: 28.9%-60.7%), 52.4% (95% CI: 34.2%-70.6%), and 36.7% (95% CI: 24.2%-49.2%), respectively ( P < 0.001) (Figure 2A). If patients were censored at the time of hematopoietic stem cell transplantation, the 5-year OS rates of these patients were 74.9% (95% CI: 65.1%-84.7%), 39.7% (95% CI: 18.7%-60.7%), 42.3% (95% CI: 11.7%-72.9%) and 0%, respectively ( P < 0.001) (Figure 2B). Patients with a negative MRD at EOI had a more favorable OS than those with a positive MRD at EOI. There was no statistically significant difference in terms of survival time between patients with MRD-lp and MRD-hp. Further, patients with MRD-vhp had the worst survival. The relapse probabilities had a similar pattern. Patients with MRD negativity at EOI had a lower 5-year CIR than those with MRD positivity at any levels. Compared to MRD-lp and MRD-hp patients, patients with MRD-vhp experienced a significantly higher rate of early relapse. However, with a longer follow-up, the 5-year cumulative incidence of relapse (CIR) did not differ significantly among patients with a positive MRD in any of the three groups, with a rate of 47.4%, 43.8%, and 49.1% in patients with MRD-lp, MRD-hp, and MRD-vhp, respectively (Figure 2C). Multivariate analysis showed that positive post-induction MRD was one of independent predictors of both OS and Disease-free survival. Conclusion Our study confirmed that MRD negativity at EOI is an independent prognostic factor of OS in adolescent and adult patients with Ph - ALL treated with pediatric-inspired regimen. Patients with MRD-lp and MRD-hp at EOI had a lower OS and a higher relapse incidence than those with MRD negativity. Therefore, an early and deep MRD clearance is important, and even extremely low MRD levels can predict poor prognosis.

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.

Adverse Prognostic Role of Copy Number Alterations and Mutations in Adults with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia

Background: The impact of copy number alterations (CNAs) or mutations on outcomes has been broadly analyzed in pediatric acute lymphoblastic leukemia (ALL). However, the magnitude of the effect was often marginal, frequently restricted to specific genetic subtypes and rarely replicated across independent cohorts in adult ALL. Aim: We tried to analyze the prognostic relevance of genetic copy number alterations and gene mutations in patients with Ph-negative ALL who were treated with modified hyper-CVAD based chemotherapy followed by allogeneic hematopoietic cell transplantation (alllo-HCT). Methods: We investigated the role of CNAs or mutations to refine risk stratification in 128 adults with newly diagnosed Philadelphia chromosome (Ph)-negative B-cell precursor ALL treated with intensive chemotherapy followed by allo-HCT for post-remission therapy. We performed multiplex ligation-dependent probe amplification (MLPA) to detect deletions of 11 genes ( IKZF1, CDKN2A/B, EBF1, ETV6, PAX5, BTG1, JAK2, RB1, PAR1, ZFY) and high throughput sequencing (HTS) of 70 gene mutations. Results: MLPA analysis showed that IKZF1 and CDKN2A/B deletions were observed in 54 (42.2%) and 52 (40.6%) patients, respectively. The remaining gene deletions were: PAX5 in 29 (22.6%), ETV6 in 22 (17.2%), BTG1 in 15 (11.7%), EBF1 in 14 (10.9%), RB1 in 13 (10.1%), JAK2 in 8 (6.2%), and PAR1 in 4 (3.1%). By HTS, NRAS (n=21, 16.4%), KRAS (n=11, 8.6%), TP53 (n=14, 10.9%), and PTPN11 (n=12, 9.4%) mutations were frequently detected. Overall, multivariate analysis for disease-free survival (DFS) and cumulative incidence of relapse (Table 1) showed that TP53 mutations (HR 5.04, 95%CI 2.29-11.30, P<0.001) and CDKN2A/B deletions (HR 1.88, 95%CI 1.10-3.31, P=0.026) were significantly associated with a poorer DFS. Patients with TP53 mutations (HR 5.64, 95%CI 1.95-16.20, P<0.001) and IKZF1 deletions (HR 1.91, 95%CI 1.09-3.31, P=0.022) had a higher relapse risk. To better define the prognostic role of CNAs, further analyses were restricted to patients excluding 14 TP53 mutations (n=114). Here, we classified patients into 4 subgroups; (1) No deletions (n=45, 39.5%), (2) IKZF1 deletion-alone (n=11, 9.6%), (3) IKZF1plus (n=40, 35.1%), and (4) CDKN2A/B±other deletions without IKZF1 deletions (n=18, 15.8%). Patients with IKZF1plus or CDKN2A/B±other deletions had an inferior DFS ( P=0.023) and higher relapse incidence ( P=0.002) than patients having no deletions. The results were similarly reproduced in patients receiving allo-HCT in first complete remission. Conclusions: Our data showed that IKZF1 or CDKN2A/B deletions and TP53 mutations may confer a poor prognosis for adult Ph-negative B-cell precursor ALL in the setting of intensive chemotherapy and allo-HCT. The combination of genomic abnormalities and minimal residual disease response may further refine risk stratification and better select patients who could benefit from novel therapeutic approaches.

A Single Center, 10-Year Experience of CALGB-10403 Regimen in AYA Population with Philadelphia-Chromosome Negative Acute Lymphoblastic Leukemia

INTRODUCTION: The use of pediatric-inspired regimens for the treatment of acute lymphoblastic leukemia (ALL) has now become the standard of care in adolescents and adults (AYA). One such regimen, CALGB 10403, had higher rates of event free survival (EFS) and overall survival (OS) compared with historical controls using adult ALL regimens. It was shown to be feasible and efficacious in fit patients up to the age of 40 (Wendy Stock et al., Blood 2019). In 2012, based on emerging data on the improved efficacy of pediatric-inspired regimens in AYA patients, CALGB 10403 was adopted as the standard-of-care regimen in this population at Karmanos Cancer Institute (KCI), an adult cancer treatment center. Here we report our single center, real world experience of using this regimen in a Philadelphia chromosome negative (Ph-) AYA population, approximately 10 years after its adoption. METHODS: We conducted a retrospective chart review of consecutive AYA (ages 18-39) patients with Ph- ALL treated with CALGB 10403 regimen between January 2012 and June 2023 at KCI. Patients who received alternative regimens due to distance from KCI were excluded. Baseline demographic, clinical and molecular characteristics were noted. High-risk cytogenetics were defined as KMT2A rearrangements, hypodiploidy with a chromosome number ≤43, and complex karyotype. Testing for Ph-like ALL was not available in most patients. Beginning in 2019, clonoSEQ assay was used to test for minimal residual disease (MRD), with MRD negativity defined at a threshold of less than 10 -4. Incidence of adverse effects and treatment related mortality were reported to describe safety. Complete response (CR) rate, OS and PFS were used as efficacy outcomes. Kaplan-Meier curves were used to estimate OS and PFS. RESULTS: A total of 17 Ph- AYA patients were treated at KCI with a median age at diagnosis of 25 years (range 18-34). Males and females had a near equal representation (47% and 53%). The patients were predominantly White (64%). The majority of patients had a good ECOG performance status of 0 or 1 (88%). The diagnosis was B-ALL in 9 (53%) and T-ALL in 8 (47%) patients. High risk cytogenetics were present in 3 (80%) of the evaluable patients. None of the patients had CNS involvement at diagnosis. Baseline laboratory parameters expressed as medians were bone marrow blast percentage 80%, WBC count 9.2 x1000/mm 3, hemoglobin 8.4 g/dL, platelets 109 x1000/mm 3, and LDH 480. The median duration of follow-up was 54 months. 15 (88%) patients had CR with induction, and MRD was negative in 4 (57%) of the 7 evaluable patients. 2 (12%) patients had primary refractory disease. One of the patients with refractory disease underwent further therapy with blinatumomab, inotuzumab, CAR-T and allogeneic stem cell transplantation and is alive at 16 months from diagnosis. Another underwent salvage with hyper-CVAD and allogeneic stem cell transplant, and is currently alive at 88 months from diagnosis. Two additional patients were MRD positive after induction (course I) but subsequently attained MRD negativity. One of these eventually relapsed 7.5 months from diagnosis with a mixed phenotypic (T/myeloid) leukemia and died at 10 months, while the other is currently under treatment. An additional patient with CR1 and unknown MRD status had CNS relapse at 35 months, underwent successful hyper-CVAD, reintroduction of intrathecal chemotherapy and allo-HSCT salvage and is alive at 122 months. The 5-year PFS and OS were 74.5% and 94% respectively and the medians were not reached for both. Noteworthy adverse effects include neutropenic fever (65%), liver function tests (LFT) abnormalities (70%), and neuropathy from vincristine (70%). Peg-asparaginase administration was associated with pancreatitis in 12%, thromboembolism in 30% and hypersensitivity reactions in 24% requiring switching to alternative forms of asparaginase products (erwinia and Rylaze). These toxicities were manageable and there were no treatment-related deaths in our cohort. CONCLUSIONS: The pediatric-inspired regimen CALGB 10403 was safe and efficacious in our AYA Ph- ALL population with no deaths due to treatment and a 5-year overall survival of 94%. Toxicities, especially from peg-asparaginase, should be closely monitored. While most patients will attain durable remission/cure, the minority with refractory or relapsed disease can still be successfully salvaged to achieve long term survival.

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 & II (days 1-22), and Re-Induction I & 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 & 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.

ALL-596 Primary Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia Among Adolescents and Young Adults Between 2017-2022 in Armenia

ALL-596 Primary Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia Among Adolescents and Young Adults Between 2017-2022 in Armenia

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.

Venetoclax and blinatumomab based chemotherapy-free treatment in a patient with Philadelphia chromosome-negative acute lymphoblastic leukemia

Venetoclax and blinatumomab based chemotherapy-free treatment in a patient with Philadelphia chromosome-negative acute lymphoblastic leukemia

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.

Safety of AFM11 in the treatment of patients with B-cell malignancies: findings from two phase 1 studies

BackgroundThe prognosis for patients with relapsed and/or refractory (R/R) non-Hodgkin’s lymphoma (NHL) or acute lymphoblastic leukaemia (ALL) remains poor, with existing treatments having significant side effects. Developed for the treatment of these cancers, AFM11 is a tetravalent, bispecific humanised recombinant antibody construct (TandAb®) designed to bind to human CD19 and CD3 and lead to the activation of T cells inducing apoptosis and killing of malignant B cells.MethodsTwo open-label, multicentre, dose-escalation phase 1 studies evaluated the safety, pharmacokinetics and activity of AFM11 in patients with R/R CD19-positive B cell NHL (AFM11-101) and in patients with CD19 + B-precursor Philadelphia-chromosome negative ALL (AFM11-102). Adverse events (AEs) were assessed and recorded; imaging (NHL) or bone marrow assessment (ALL) were used to evaluate response. Additional pharmacodynamic assays undertaken included cytokine release analysis and B-cell and T-cell depletion.ResultsIn AFM11-101, 16 patients with R/R NHL received AFM11 in five different dose cohorts. Of which, 14 experienced drug-related treatment-emergent AEs (TEAEs) [including five serious AEs (SAEs)], five patients experienced dose-limiting toxicity (DLT) and ten patients discontinued the study. The high number of neurological events led to a decrease in infusion frequency during the study. No objective response to treatment was observed. In AFM11-102, 17 patients with R/R ALL received AFM11 in six different dose cohorts. Thirteen patients experienced drug-related TEAEs (including four SAEs), DLTs occurred in two patients and five patients discontinued the study. An objective response was recorded in three patients. The maximum tolerated dose could not be determined in either study due to early termination.ConclusionsAFM11 treatment was associated with frequent neurological adverse reactions that were severe in some patients. In ALL, some signs of activity, albeit short-lived, were observed whereas no activity was observed in patients with NHL; therefore, further clinical development was terminated.Trial registrationNCT02106091. Safety Study to Assess AFM11 in Patients With Relapsed and/or Refractory CD19 Positive B-cell NHL. Registered April 2014. NCT02848911. Safety Study to Assess AFM11 in Patients With Relapsed or Refractory Adult B-precursor ALL. Registered July 2016.

Hematopoietic stem cell transplantation for adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in the first complete remission

The treatment outcomes for adult Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) have improved with the introduction of pediatric protocols. On assessing long-term survivors of chemotherapy who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), it was found that these patients had good performance status and few complications. Therefore, in the first complete remission (1CR) of ALL, allo-HSCT is indicated for patients in whom the results of chemotherapy are predicted to be poor. In adolescent and young adult (AYA) patients with ALL, allo-HSCT is recommended in the 1CR if end of consolidation measurable residual disease (MRD) is positive. In adults with ALL (non-AYA patients), if end of induction MRD is negative, chemotherapy should be continued and allo-HSCT is not recommended. In the future, it is necessary to perform a comprehensive evaluation of individual patients that considers MRD, as well as the initial tumor burden and biological features of leukemic cells.

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

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.

Vincristine Sulfate Liposome Injection with Bendamustine and Rituximab as First-Line Therapy for B-Cell Lymphomas: A Phase I Study

BackgroundWe conducted an investigator-initiated, phase I trial of vincristine sulfate liposomal injection (VSLI) in combination with bendamustine and rituximab (BR) for indolent B-cell (BCL) or mantle cell lymphoma.MethodsParticipants received 6 cycles of standard BR with VSLI at patient-specific dose determined by the Escalation with Overdose Control (EWOC) model targeting 33% probability of dose-limiting toxicity (DLT). Maximum tolerated dose (MTD) was the primary endpoint; secondary endpoints included rates of adverse events (AEs), overall response rate (ORR), and complete response (CR). Vincristine sulfate liposomal injection is FDA approved for the treatment of patients with recurrent Philadelphia chromosome-negative (Ph−) acute lymphoblastic leukemia (ALL).ResultsAmong 10 enrolled patients, VSLI was escalated from 1.80 to 2.24 mg/m2, with one DLT (ileus) at 2.04 mg/m2. Two patients discontinued VSLI early. The most common AE included lymphopenia (100%), constipation, nausea, infusion reaction (each 60%), neutropenia, and peripheral neuropathy (50%). Grade 3/4 AE included lymphopenia (90%), neutropenia (20%), and ileus (10%), with prolonged grade ≥2 lymphopenia observed in most patients. Calculated MTD for VSLI was 2.25 mg/m2 (95% Bayesian credible interval: 2.00-2.40). Overall response was 100% with 50% CR. With median follow-up 26 months, 4/10 patients experienced recurrence and 1 died.ConclusionVincristine sulfate liposomal injection at 2.25 mg/m2 can be safely combined with BR for indolent B-cell lymphoma, but given observed toxicities and recurrences, we did not pursue an expanded cohort.Clinical Trials Registration Number: ClinicalTrials.gov identifier NCT02257242.