Chromosome-negative B-cell Acute Lymphoblastic Leukemia Research Articles

Phase 2 Trial of Mini-Hyper-CVD Plus Inotuzumab Ozogamicin, with or without Blinatumomab, in Older Patients with Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia

Background The introduction of inotuzumab ozogamicin (InO) and blinatumomab (blina) has drastically improved the overall survival (OS) of patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). Older patients with B-ALL have worse outcomes compared with younger patients due to the poor-risk biology of their disease and their inability to tolerate intensive chemotherapy. We aim to study the incorporation of InO and blina with low intensity chemotherapy in older patients with newly diagnosed (ND) B-ALL. Methods Adults ≥60 years with ND Philadelphia chromosome (Ph)-negative B-ALL who were untreated or had received up to two cycles of previous therapy were eligible. Other inclusion criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of ≤3 and adequate organ function. Patients with central nervous system (CNS) disease were eligible. Patients received mini-Hyper-CVD (mHCVD, cyclophosphamide 150mg/m 2 q12h D1-3, dexamethasone 20mg daily D1-4, 11-14, and vincristine 2mg D1, 8 alternating with methotrexate (MTX) 250mg/m 2 D1 & cytarabine 500mg/m 2 q12h D2, 3) for up to 8 cycles. Eight doses of intrathecal (IT) MTX /cytarabine were given for CNS prophylaxis; patients with CNS disease had IT hydrocortisone, MTX, and cytarabine twice weekly till CNS clearance, then weekly x4. Eight doses of rituximab 375mg/m 2 were given on D1, 8 of C1-4 if CD20 was ≥20% by flow cytometry. Initially, InO was given at 1.3-1.8mg/m 2 on D3 of C1 and 1.0-1.3mg/m 2 on D3 in C2-4. The protocol was amended from patient 50 such that InO was given in fractionated doses with a maximum cumulative dose of 2.7mg/m 2 (0.6 mg/m 2 on D2 of C1, 0.3 mg/m 2 on D8 of C1, then 0.3 mg/m 2 on D2 and D8 of C2-4). Ursodeoxycholic acid was given to all patients. Four cycles of blina 28µg/day replaced C5-8 of mHCVD + InO. Maintenance was initially with vincristine 2mg D1, prednisolone 50mg daily D1-5, 6-mercaptopurine 50mg BID & MTX 10mg/m 2 weekly (POMP) for three years. After the protocol amendment, this was reduced to 12 cycles of POMP, with one cycle of blina given after every three POMP cycles (total four blina cycles). Results 83 patients with a median age of 68y (range, 60 - 87; ≥70y, 34%) were enrolled (Table 1). Several patients had high-risk features: 25 (39%) harbored TP53 mutations, 9 (18%) had a Ph-like signature, and 19 (23%) had high-risk cytogenetics (12 low hypodiploidy/near triploidy, 3 tetraploidy, 3 complex and 1 t(4;11)). 77 patients were not in CR at enrollment and evaluable for response. 76 (99%) responded, with 69 (90%) attaining CR. Among responders, 60 (79%) and 71 (94%) patients had no detectable minimal residual disease (MRD) by flow cytometry after C1 and overall, respectively. No early deaths were observed. After a median follow-up of 88 months (IQR, 41-120), the median overall survival (OS) was 56 months (95%CI, 28-85), and the median progression-free survival (PFS) was 47 months (95% CI, 21-72). The 5-year continuous remission duration (CRD) and OS rates were 78% and 49%, respectively. The 5-year OS for patients aged 60-69 without adverse cytogenetics (n=40), age 60-69 with adverse cytogenetics (n=15), age ≥70 without adverse cytogenetics (n=24) and age ≥70 with adverse cytogenetics (n=4) were 73%, 27%, 39% and 0%, respectively. Five (6%) patients underwent allogeneic stem cell transplantation (ASCT) in first CR, 12 (15%) relapsed, 33 (40%) remain in ongoing continuous remission without ASCT, and 33 (40%) died in remission. Of the 12 relapsing patients, 5 had extramedullary disease, all with CNS involvement. 12 (14%) patients died due to progressive disease at a median of 23 (range 2 - 78) months; these patients had a median age of 64 (range 60 - 79) years. Of the 33 who died in remission, nine were due to secondary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). The median age of these patients was 71 years (range, 64 - 87), with a median time to MDS/AML of 34 months (range, 7 - 75). Fourteen deaths in CR were due to treatment-related complications (9 sepsis, 3 veno-occlusive disease (VOD), 2 ASCT). Six (7%) patients developed veno-occlusive disease, 4/49 (8%) in the pre-amendment group and 2/34 (6%) in the post-amendment group. Conclusion Older patients with ND Ph-negative ALL treated with mHCVD plus InO, with or without blina had excellent response rates and deep remissions. However, further adjustment of the regimen is needed, especially in patients ≥70 years.

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.

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

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

Venetoclax, Cladribine Plus Low-Dose Cytarabine Achieved High Remission in Patients with Relapse/Refractory Acute Leukemia: Preliminary Results of a Phase II Study

Background: Patients with relapse/refractory acute leukemia often show resistance to conventional chemotherapy and have dismal prognosis. Salvage therapy using venetoclax combined with hypomethylating agents achieved an overall response rate of approximately 40% in relapsed/refractory (R/R) acute myeloid leukemia (AML) patients. Cladribine is an adenosine deaminase resistant analog of adenosine. The efficacy of cladribine and venetoclax in R/R acute leukemia (AL) has not been reported. Here, we report preliminary results of venetoclax, cladribine plus low-dose cytarabine (CAV regimen) in the treatment of R/R AL. This study was registered at ClinicalTrials.gov (NCT05190549). Methods: 30 patients were enrolled from March 2021 to May 2022 at the First Affiliated Hospital of Soochow University. 21 patients were diagnosed with R/R AML (6 patients with favorable risk, 2 patients of intermediate risk and 13 patients with high risk at diagnosis) (Table 1). Seven patients were diagnosed with R/R Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia (ALL) (5 with high risk and 4 patients of unknown). The CAV regimen consisted of cladribine 5 mg/m2/day from day 1 to day 3 or day 5, cytarabine 20mg/m2, q12h for 7-10 days, venetoclax 100mg d1, 200 d2, 400 mg/day from day 3 to day 28 (The exact number of days is at the investigator's decision). Bone marrow evaluation were performed within 1 week at the end of treatment. Results: The median age of enrolled patients were 39 in AML and 35 in ALL. 13/21 (66.9%) of AML patients and 5/9 (51.6%) of ALL patients had high-risk cytogenetics at diagnosis. All patients showed early relapse (less than 12-months from CR1). After one cycle of the CAV regimen, the overall response rate (ORR=CR+CRi+MLFS+PR) for AML was 90.5%. The rate of CR/CRi/MLFS was 81% in AML and CR/CRi was 55.6% in ALL. The estimated 1-year overall survival (OS) in AML and ALL was 91.7% and 100%, respectively. The event-free survival (EFS) for AML and ALL were 74.9% and 87.5%, respectively. The median OS, EFS of one year for all 30 patients were not reached. There was no significant statistical difference of disease type in OS (P=0.162) and EFS (P=0.935). During the treatment with CAV regimen, 7 patients (33.3%) developed grade 1 to 2 elevated transaminases. 5 patients (23.8%) developed grade 1 to 2 nausea and vomiting and 1 patient(7.4%) developed grade 3 nausea and vomiting. 3 patients(14.3%) developed grade 1 to 2 skin pruritus and rash. During a median follow-up of 116-days, 3 patients died of disease relapse(Picture1,2). There was no CAV treatment-related mortality. Conclusion: The CAV regimen was an effective and safe salvage strategy in relapse/ refractory acute leukemia. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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

Outcomes After Retreatment With Inotuzumab Ozogamicin for Relapsed/Refractory Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia.

Article Tools CASE REPORTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/PO.22.00353 JCO Precision Oncology no. 6 (2022) e2200353. Published online October 14, 2022. PMID: 36240471 Outcomes After Retreatment With Inotuzumab Ozogamicin for Relapsed/Refractory Philadelphia Chromosome–Negative B-Cell Acute Lymphoblastic Leukemia Juan Alban , MD1xJuan AlbanSearch for articles by this author; Adam DuVall , MD, MPH2xAdam DuVallSearch for articles by this author; Sandeep Gurbuxani , MBBS3xSandeep GurbuxaniSearch for articles by this author; Wendy Stock , MD2xWendy StockSearch for articles by this author; and Anand Ashwin Patel , MD2xAnand Ashwin PatelSearch for articles by this author Show More 1Department of Medicine, University of Chicago, Chicago, IL2Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL3Section of Hematopathology, Department of Pathology, University of Chicago, Chicago, IL https://doi.org/10.1200/PO.22.00353 First Page Full Text PDF Figures and Tables Supplements © 2022 by American Society of Clinical OncologyAUTHOR CONTRIBUTIONSConception and design: All authorsCollection and assembly of data: Juan Alban, Sandeep Gurbuxani, Anand Ashwin PatelData analysis and interpretation: All authorsManuscript writing: All authorsFinal approval of manuscript: All authorsAccountable for all aspects of the work: All authorsAUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).Juan AlbanEmployment: AbbVie (I)Leadership: AbbVie (I), SpringWorks Therapeutics (I)Adam DuVallConsulting or Advisory Role: Jazz PharmaceuticalsSpeakers' Bureau: Jazz PharmaceuticalsSandeep GurbuxaniConsulting or Advisory Role: AbbViePatents, Royalties, Other Intellectual Property: Royalties from UpToDate for contributions to various topicsWendy StockHonoraria: AbbVie, PfizerConsulting or Advisory Role: Jazz Pharmaceuticals, Kite, a Gilead Company, Kura Oncology, GlaxoSmithKline, Morphosys, Pfizer, Servier, Deciphira, BEAm, Newave Pharmaceutical, AstraZeneca, Kronos Bio, Pluristem TherapeuticsPatents, Royalties, Other Intellectual Property: Royalties for a chapter in Up to DateTravel, Accommodations, Expenses: PfizerAnand Ashwin PatelResearch Funding: Bristol Myers Squibb/Celgene (Inst), Servier (Inst), Pfizer (Inst)No other potential conflicts of interest were reported.

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.

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

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

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

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

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

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

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

Updated Results from a Phase II Study of Hyper-CVAD with Sequential Blinatumomab in Adults with Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia

Updated Results from a Phase II Study of Hyper-CVAD with Sequential Blinatumomab in Adults with Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia

Unmanipulated haploidentical hematopoietic stem cell transplantation is an excellent option for children and young adult relapsed/refractory Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia after CAR-T-cell therapy.

Although chimeric antigen receptor T-cell (CAR-T) therapy produces a high complete remission rate among patients with relapsed/refractory B-cell acute lymphoblastic leukemia, relapse remains an urgent issue. It is uncertain whether consolidative haploidentical-allogeneic hematopoietic stem cell transplantation (haplo-HSCT) is suitable for achieving sustainable remission. Therefore, we aimed to assess the efficacy and safety of bridging CAR-T therapy to haplo-HSCT. Fifty-two patients with relapsed/refractory Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia who underwent haplo-HSCT after CAR-T therapy were analyzed. The median time from CAR-T therapy to haplo-HSCT was 61 days. After a median follow-up of 24.6 months, the 1-year probabilities of event-free survival, overall survival, and cumulative incidence of relapse were 80.1% (95% confidence interval (CI), 69.0-90.9), 92.3% (95% CI, 85.0-99.5), and 14.1% (95% CI, 10.7-17.4), respectively, while the corresponding 2-year probabilities were 76.0% (95% CI, 64.2-87.7), 84.3% (95% CI, 74.3-94.3), and 19.7% (95% CI, 15.3-24.0), respectively. No increased risk of 2-year cumulative incidence of graft-versus-host disease, treatment-related mortality, or infection was observed. A pre-HSCT measurable residual disease-positive status was an independent factor associated with poor overall survival (hazard radio: 4.201, 95% CI: 1.034-17.063; P = 0.045). Haplo-HSCT may be a safe and effective treatment strategy to improve event-free survival and overall survival after CAR-T therapy.

Hyper-CVAD and Sequential Blinatumomab in Adults with Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia: Results from a Phase II Study

Hyper-CVAD and Sequential Blinatumomab in Adults with Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia: Results from a Phase II Study

Frontline Blinatumomab in Older Adults with Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia.

Outcomes of acute lymphoblastic leukemia (ALL) in older adults treated with chemotherapy are poor. The CD19/CD3 bispecific T-cell engager (BiTE) antibody blinatumomab is approved for refractory, relapsed or minimal/measurable residual disease (MRD)-positive B-cell ALL, but there is little experience in the upfront setting, including in older patients. We retrospectively analyzed outcomes of blinatumomab monotherapy in five newly diagnosed Philadelphia chromosome-negative B-cell ALL patients over 70 years. Three had cytokine release syndrome, treated with dexamethasone and/or tocilizumab, and four patients had neurotoxicity, treated with dexamethasone, without blinatumomab interruption. All five achieved complete remission (CR) after cycle one, three with undetectable MRD. All five were alive at 8 to 15 months. Three remained in MRD-negative CR. Two relapsed after cycle 3, one with extramedullary disease. In our small cohort of patients over 70 years, blinatumomab was safe initial therapy and produced a high response rate.

Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia in Adolescents and Young Adults.

Adolescents and young adults (AYAs) with Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) represent a unique patient population with a disproportionate survival disadvantage compared with younger children. Substantial progress has been made as we began to understand and address the multifaceted drivers behind this outcome disparity. New insights into the biology of B-cell ALL have uncovered distinct genetic characteristics more commonly found in AYAs that affect prognosis. Dramatic improvements in survival have been achieved with the use of pediatric-inspired protocols in the front-line setting, as well as antibody-based and chimeric antigen receptor T-cell therapies in the relapsed and refractory setting. Guided by the incorporation of minimal residual disease testing to inform clinical decision making, these represent major paradigm shifts in management. Efforts to design clinical trials geared toward AYAs and to enroll AYAs in available clinical trials will ensure ongoing progress. Holistic care of AYAs with ALL further involves recognition of psychosocial issues arising as a consequence of their diagnosis and the delivery of age-appropriate supportive care.

Successful Treatment of Refractory Acute Lymphoblastic Leukemia with Tisagenlecleucel in the Setting of Life-Threatening Infection

Tisagenlecleucel is a CD19 directed immunotherapy approved for the treatment of young patients with relapsed or refractory precursor B-cell acute lymphoblastic leukemia (ALL). The most important toxicity related to tisagenlecleucel therapy is cytokine release syndrome (CRS). CRS is an exaggerated systemic inflammatory response that occurs frequently along with T-cell expansion following the administration of tisagenlecleucel. Tisagenlecleucel guidelines recommend delaying treatment when an active infection is present due to the concern that the pre-existing inflammatory response associated with infection may predispose patients to severe CRS. We describe two cases where tisagenlecleucel was successfully administered to patients in the setting of life-threatening infection. Patient 1 is a 23-year-old Caucasian male with refractory Philadelphia chromosome negative B-cell ALL who had received prior treatment with chemotherapy, blinatumomab, inotuzumab ozogamicin and a haploidentical stem cell transplant (SCT) followed by multiple Zalmoxis infusions. Five months following SCT he relapsed. At relapse, he underwent leukapheresis followed by bridging chemotherapy with ifosfamide and etoposide. He developed severe neutropenia and respiratory failure associated with a right lower lung consolidation. A biopsy demonstrated a mucormycosis infection and he required surgical debridement including resection of portions of the lung, diaphragm and liver. At this time, he had 92% blasts in the bone marrow. Eleven days after his surgery he received tisagenlecleucel despite being persistently febrile. Prior to the infusion, he received a modified lymphodepleting chemotherapy regimen including two days of fludarabine and cytarabine. Due to severe neutropenia, he was receiving granulocyte transfusions. These were discontinued prior to the infusion and resumed after 12 days. CRP and ferritin the day prior to infusion were 26.2 mg/dL and 18,419 ng/mL. He remained persistently febrile for 13 days post-infusion. He received a single dose of tociluzimab 7 days following his infusion due to high fevers. He did not require any treatment with corticosteroids for CRS. The absolute neutrophil count recovered to &gt;500x103/µL at 31 days post infusion. A bone marrow aspirate done 26 days post-infusion did not show any evidence of leukemia by multicolor flow cytometry (MFC). He remains alive without evidence of disease 11 months after treatment with tisagenlecleucel. Patient 2 is a 4-year-old Hispanic female with refractory B-cell ALL found to have a TP53 deletion and t(1;19). She had received prior treatment with chemotherapy, blinatumomab and local radiation therapy to the site of extramedullary disease found in the left maxillary sinus at relapse. She underwent leukapheresis and received bridging chemotherapy with mercaptopurine and methotrexate. After 3 days of lymphodepleting chemotherapy she developed septic shock and E. Coli bacteremia. She became severely ill requiring continuous renal replacement therapy for 5 days and extracorporeal membrane oxygenation (ECMO) for 6 days. Shortly after ECMO decannulation she developed fever and was found to have multiple pulmonary opacities concerning for fungal infection. Blasts were noted in the peripheral blood. Sixteen days after presenting with septic shock and 11 days from ECMO she received tisagenlecleucel. CRP at the time of infusion was 22.9 mg/dL. She developed persistent fevers post-infusion for 17 days. She received two doses of tociluzimab 20- and 21-days post-infusion due to recurrence of high fever and reactive lymphadenopathy with third spacing and concern for renovascular compromise. She did not require any treatment with corticosteroids for CRS. Bone marrow aspirate done 32 days post-infusion did not show any evidence of leukemia by MFC. The absolute neutrophil count recovered to &gt;500x103/µL at 59 days post infusion. The patient remained without evidence of disease for 7 months following treatment but died due to infectious complications with persistent pancytopenia. Tisagenlecleucel is a potentially life-saving treatment for relapsed and refractory B-cell acute lymphoblastic leukemia in children and young adults 24 years of age or younger. Tisagenlecleucel is an option for the treatment of patients with active infection and/or inflammation with progressive leukemia when no other therapeutic alternative exists. Disclosures August: Novartis Pharmaceuticals: Speakers Bureau. Myers:Novartis Pharmaceuticals: Consultancy, Speakers Bureau.

Economic burden associated with adverse events of special interest in patients with relapsed Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia in the United States

ABSTRACTBackground: Infections, cytopenia, and gastrointestinal (GI) toxicity are adverse events of special interest (AESI) affecting most relapsed Philadelphia chromosome–negative (Ph−) B-cell acute lymphocytic leukemia (ALL) patients. This study quantified real-world rates and economic burden of these events among relapsed Ph− B-cell ALL patients in the United States.Methods: Adults with relapsed Ph− B-cell ALL during 1 April 2009–31 October 2016 were selected from MarketScan® healthcare claims databases. Outcomes included proportions of patients with AESIs and AESI-related costs during 100 days after relapsed hospitalization.Results: Of 400 relapsed Ph− B-cell ALL patients, 92.5% experienced ≥1 AESI during the median 100-day follow-up, of which 64.6% had infections, 94.6% cytopenia, and 46.2% GI toxicities. Mean (SD; median) AESI-related total cost per patient during follow-up was $197,213 ($308,551; $105,731), with a mean of 2 AESI-related hospitalizations comprising 32.2 inpatient days. Mean (SD; median) healthcare costs were highest for infections ($164,461 [$347,083; $64,528]), followed by cytopenia ($125,210 [$165,141; $67,475]) and GI events ($11,652 [$40,231; $1349]).Conclusion: The economic burden of AESIs is substantial, with infections the most expensive, followed by cytopenia and GI toxicity. New therapies that can improve outcomes in relapsed Ph− B-cell ALL while offering a favorable safety profile are needed.

Expression of CD13 in Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia and its clinical significance

Objective To analyze the immunophenotypes of B-cell acute lymphoblastic leukemia(B-ALL) and correlation between the expression of CD13 and clinical, hematologic and biological parameters in patients with Philadelphia chromosome-negative(Ph-) B-ALL. Methods Multiparameter flow cytometry was used to analyze the immunophenotypes of the bone marrow blasts in 111 cases of adult and 32 cases of childhood B-ALL. Results The positive rates of CD13 and CD33 in childhood B-ALL patients were no differences compared with those in adult patients [31.3%(10/32) vs 19.8%(22/111), 18.8%(6/32) vs 29.7%(33/111), both P>0.05]. In de novo Ph- B-ALL, the frequency of CD13 in childhood patients was higher than that in adult patients [32.3% (10/31) vs 9.4% (6/64), P 0.05). Difference on time of relapse was found between CD13+ and CD13- groups in childhood Ph- B-ALL patients[(111±16) d vs (683±57) d, P<0.000 1]. The time of relapse between childhood and adult CD13+ Ph- B-ALL cases had statistical difference [(111±16) d vs (319±16) d,P<0.000 1]. Conclusions The positive rate of CD13 is higher in childhood Ph- B-ALL patients than that in adult Ph- B-ALL patients. CD13+ Ph- B-ALL patients, in particular, childhood Ph- CD13+ patients are more likely to relapse. Key words: Leukemia, B lymphoblastic, acute; Multiparameter flow cytometry; Immunophenotyping; CD13

Blinatumomab for Relapsed/Refractory Acute Lymphocytic Leukemia: A Single Center Experience

Introduction: Patients with relapsed/refractory acute lymphoblastic leukemia (ALL) have a poor prognosis and limited treatment options. Blinatumomab was approved in 2014 for the treatment of relapsed/refractory Philadelphia chromosome-negative B-cell ALL. The largest published study of 189 patients with relapsed/refractory B-ALL showed a complete remission/complete remission without hematologic recovery of 43%. Here we report our single center experience in 7 patients with relapsed/refractory B-ALL treated with blinatumomab.Methods: We reviewed the charts of 7 adult patients with relapsed/refractory ALL. All patients were treated with blinatumomab 9 mcg daily as a continuous infusion on days 1-7, followed by 28 mcg daily as a continuous infusion on days 8 - 28 of a 6 week cycle. For cycle 2, 28 mcg daily as continuous infusion was given on days 1 - 28 of a 6 week cycle.Patients: The median age was 48 (range 23-70) and included 5 males/2 females. One patient had persistent disease after two cycles of induction (pt 4), 6 had relapsed B-ALL, and 4/6 had prior allogeneic stem cell transplant (SCT).Results: Two patients (28.6%) had complete remission and received allogeneic SCT in CR, 3 received additional therapy, 2 patient expired soon after blinatumomab. Three of 7 patients (42.9%) were unable to complete 2 cycles: patient 1 for progressive disease on cycle 1 day 13; patient 2 for trismus on cycle 2 day 17; patient 7 on cycle 2 day 8 for mental status changes which recurred after re-challenge. Other toxicities were relatively minor (rigors,headache). One patient (pt 7) developed a venous thromboembolism during the 2 week break period between cycles 1 and 2. Five patients are alive: three in CR post-SCT, one in CRi to other salvage therapy, and one on active therapy in a clinical trial.Conclusion: The observed response rates in our single center experience are not as high as reported in the clinical trials of blinatumomab in relapsed/refractory B-ALL. We saw responses in patients with MRD as well as one patient who had received 5 lines of prior therapy. It is not uncommon to see responses in clinical practice lower than those observed in a clinical trial. Studies are ongoing to determine the benefit of blinatumomab in other B-ALL settings. Our observed rates of CRS and neurologic toxicity were lower than those previously reported, and our experience suggests that it is relatively well-tolerated. Blinatumomab may be beneficial for some patients with B-ALL and provide a bridge to SCT for those who respond.Table 1PtSexAgePrior treatmentsPrior SCTBone marrow blast % prior tx# of cycles &Reason for discontinuationToxicityBone marrow blast % after txOutcome1M701 4 cycles of hyperCVAD, achieved CR Relapse at 9 months post-txN74%< 1 Stopped for progressive diseaseGrade 1 CRS99% blasts in peripheral blood on day 13Other salvage chemotherapy Expired2F624 Allogeneic SCT in CR1 Relapse 3.5 years post-SCTY70%<2 Stopped on day 17 for sxTrismus83% after cycle 2Clinical trial3M235 Allogeneic SCT in CR2 Relapse 1 year post-SCTY1%1 Stopped for alternative clinical trial therapyHSV-1 lesions Rash2%CAR-T cells followed by second SCT4F491 CALGB induction x 2 cycles with 3% persistent blastsN3%1 Stopped for allogeneic SCTNoneMRD negativeMatched sibling donor SCT5M644 Haplo-SCT in CR1 Relapse 9 months post-SCT FLAG salvage to CRi Relapse 4 months post-FLAGY70%2Rigors93%Clinical trial6M445 hyperCVAD + maintenance, Relapse 1 year post-maintenance, Salvage with multiple regimens, persistent diseaseN6%2Headache1%Haplo-SCT7M254 Pediatric induction, consolidation, maintenance Relapse 2 years post-maintenance, Reinduction achieved CR2, Allo-SCT in CR2 Relapse 1 year post-SCTY71%<2 Stopped on day 8 for mental status changesMental status changes35%Hospice Expired DisclosuresNo relevant conflicts of interest to declare.