Chromosome-positive ALL Research Articles

A Multicenter Analysis of Allogeneic Transplant Outcomes in Adults with Philadelphia-Like B-Cell Acute Lymphoblastic Leukemia in First Complete Remission

Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subset of B-cell ALL with a poor prognosis with conventional therapies. Diagnostic challenges and lack of standardized treatment protocols contribute to suboptimal outcomes. Additionally, while allogeneic hematopoietic cell transplantation (HCT) is frequently recommended in adults with Ph-like ALL given its high-risk nature, data supporting its role remains limited. We conducted a multicenter retrospective study evaluating outcomes of adult patients undergoing HCT in first complete remission (CR1) for Ph-like ALL compared to Philadelphia chromosome positive ALL (Ph-pos) and other B-cell Philadelphia negative (Ph-neg) ALL. Data was collected from five academic centers across the US, focusing on HCT outcomes for patients with ALL. Patients undergoing HCT in CR1 between 2006 and 2021 were included. Among 673 patients, 83 (12.3%) had Ph-like ALL, while 271 (40.3%) had Ph-pos and 319 (47.4%) had Ph-neg ALL. Outcomes following HCT in CR1 for Ph-like ALL were comparable to Ph-neg ALL, with no significant differences in 3-year overall survival (66% vs. 59%, P = .1), progression-free survival (59% and 54%, P = .1), or relapse rates (22% vs. 20%, P = .7). In contrast, Ph-pos ALL had superior outcomes; 3-year OS (75%, P < .001), PFS (70%, P = .001) and relapse (12%, P = .003), this is likely attributed to tyrosine kinase inhibitor therapy. Our study suggests that HCT, coupled with effective 2nd line therapies can possibly mitigate the poor prognosis associated with Ph-like ALL and offers promising outcomes for patients with Ph-like ALL.

ALL-766 Asciminib as a Bridge to Allogenic Transplant in 3 Patients With Relapsed/Refractory Philadelphia Chromosome-positive ALL or CML Lymphoid Blast Crisis Refractory/Intolerant to Ponatinib

ALL-766 Asciminib as a Bridge to Allogenic Transplant in 3 Patients With Relapsed/Refractory Philadelphia Chromosome-positive ALL or CML Lymphoid Blast Crisis Refractory/Intolerant to Ponatinib

Asciminib as a Bridge to Allogenic Transplant in 3 Patients With Relapsed/Refractory Philadelphia Chromosome-Positive ALL or CML Lymphoid Blast Crisis Refractory/Intolerant to Ponatinib

Asciminib as a Bridge to Allogenic Transplant in 3 Patients With Relapsed/Refractory Philadelphia Chromosome-Positive ALL or CML Lymphoid Blast Crisis Refractory/Intolerant to Ponatinib

Significance of Measurable Residual Disease in Adult Philadelphia Chromosome-Positive ALL: A GRAAPH-2014 Study.

BCR::ABL1 quantification is widely regarded as the standard for monitoring measurable residual disease (MRD) in Philadelphia chromosome-positive (Ph+) ALL. However, recent evidence of BCR::ABL1 multilineage involvement questions the significance of BCR::ABL1 MRD. We aimed to define the prognostic role of MRD as assessed by BCR::ABL1 or lymphoid-specific immunoglobulin/T-cell receptor (IG/TR) gene markers. We conducted BCR::ABL1 and IG/TR quantification after each treatment cycle in 264 patients treated in the GRAAPH-2014 trial, which used four cycles of reduced-intensity chemotherapy with nilotinib, followed by hematopoietic stem-cell transplantation (HSCT). Comparing BCR::ABL1 and IG/TR MRD revealed residual BCR::ABL1-positive non-ALL cells in 98 (43%) of 228 patients, defining multilineage Ph+ ALL. Despite poorer BCR::ABL1 responses, patients with multilineage Ph+ ALL had similar disease-free survival (DFS; hazard ratio [HR], 0.83 [95% CI, 0.49 to 1.41]; P = .50). Although BCR::ABL1 response failed to predict outcomes, IG/TR positivity (≥0.01%) was strongly associated with lower DFS (after cycle 2, HR, 2.49 [95% CI, 1.40 to 4.40]; P = .002; after cycle 4, HR, 4.13 [95% CI, 1.82 to 9.38]; P = .001). In multivariable analysis, both IG/TR positivity after cycle 2 and initial WBC count ≥30 × 109/L predicted poorer DFS, enabling to define a high-risk group having a 4-year DFS of 56.5% compared with 87.6% (HR, 3.72 [95% CI, 1.93 to 7.15]; P < .001). Moreover, allogeneic HSCT significantly improved DFS in the high-risk group (HR, 0.33 [95% CI, 0.18 to 0.60]; P < .001), whereas the standard-risk group had favorable outcomes regardless of allogeneic HSCT. Our findings challenge the significance of BCR::ABL1 monitoring in adult Ph+ ALL and demonstrate the prognostic role of IG/TR MRD. This study provides a framework for using MRD to guide treatment strategies in adults with Ph+ ALL.

Results of the Simultaneous Combination of Ponatinib and Blinatumomab in Philadelphia Chromosome-Positive ALL.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In this analysis, we update our experience with the chemotherapy-free regimen of blinatumomab and ponatinib in 60 patients with newly diagnosed Philadelphia chromosome (Ph)-positive ALL. At a median follow-up of 24 months, the complete molecular response rate by reverse transcriptase-polymerase chain reaction was 83% (67% at the end of course one), and the rate of measurable residual disease negativity by next-generation clono-sequencing was 98% (45% at the end of course one). Only two patients underwent hematopoietic stem cell transplantation (HSCT). Seven patients relapsed: two with systemic disease, four with isolated CNS relapse, and one with extramedullary Ph-negative, CRLF2-positive pre-B ALL. The estimated 3-year overall survival rate was 91% and event-free survival rate was 77%. Three patients discontinued blinatumomab because of adverse events (related, n = 1; unrelated, n = 2) and nine discontinued ponatinib because of cerebrovascular ischemia, coronary artery stenosis, persistent rash, elevated liver function tests with drug-induced fatty liver, atrial thrombus, severe arterial occlusive disease of lower extremities, pleuro-pericardial effusion, and debilitation. In conclusion, the simultaneous combination of ponatinib and blinatumomab is a highly effective and relatively safe nonchemotherapy regimen. This regimen also reduces the need for intensive chemotherapy and HSCT in first remission in the majority of patients.

Short-Term Blinatumomab As a Bridge Therapy for Hematopoietic Stem Cell Transplantation in B-Cell Acute Lymphoblastic Leukemia with Low Leukemia Burden

Introduction The influence of pre-transplant leukemic load on relapse and long-term survival is well-documented among patients with B-cell acute lymphoblastic leukemia (B-ALL). Blinatumomab, a bispecific T cell engager, has shown promising results as an effective treatment for relapsed B-ALL. However, the dosage (28μg/day) and duration (28 days of continuous infusion) of blinatumomab have been predominantly determined in a relapsed leukemia context. Therefore, in the minimal residual disease (MRD) scenario, the standard dosing may exceed the required amount, potentially leading to increased toxicity, delays in transitioning to the scheduled transplant, and superfluous economic expenditure. Methods We enrolled B-ALL patients with ≤10% MRD who were slated for allogeneic hematopoietic stem cell transplantation (ASCT). MRD was quantified via multi-parameter flow cytometry or polymerase chain reaction (PCR) for the target gene. Blinatumomab therapy began at 8 μg/day, gradually escalating to 28 μg/day over only 5-10 days. Bone marrow cells were harvested post-blinatumomab therapy. Upon acquiring MRD negativity, patients proceeded to the transplantation protocol. All patients underwent myeloablative conditioning with chidamide, fludarabine, cytarabine, and busulfan. Peripheral stem-cell grafts were harvested from HLA-matched sibling donors (MSD), matched unrelated donors (MUD), or haploidentical donors (HID). Post-transplantation acute GVHD prophylaxis consisted of cyclophosphamide and cyclosporine. For HID transplant recipients, mycophenolate mofetil was added from day +5 to day +35. Follow-up examinations were scheduled at +1, +2, +3, +4, +6, +9, +12, +18, and +24 months post-transplant. Results Our study cohort comprised 20 patients (13 females, 7 males), median age 35.5 years (range 15-58). Patient and disease characteristics are summarized in Table 1. During the blinatumomab therapy, 8 patients (40%) experienced grade 1 cytokine release syndrome (CRS), and 1 patient (5%) experienced grade 2 CRS, with no instances of grade 3 or higher CRS observed. All patients achieved complete remission (CR) and MRD clearance evaluated by flow cytometry following blinatumomab treatment. Eleven patients were diagnosed with Philadelphia chromosome-positive ALL, and 5 of them didn't achieve MRD clearance evaluated by PCR. Allo-SCT was conducted following blinatumomab at a median interval of 5.5 days (range 1-29) using MSD in 4 patients, MUD in 2 patients, and HID in 14 patients. The median time to neutrophil and platelet engraftment was 12 days (range 9-17) and 13 days (range 9-28), respectively. The median follow-up duration was 10.2 months (range 2-21.7). By day +30 post-ASCT, all patients achieved CR and MRD clearance with full donor chimerism. Acute GVHD (aGVHD) (grades II-IV) and (grades III-IV) incidences were recorded at 10.0% and 5.3% respectively (Figure 1A). One fatality occurred due to COVID-19-associated pulmonary aspergillosis 7.2 months post-transplantation. Among the 18 evaluable patients, the estimated 1-year cumulative incidence of chronic GVHD (cGVHD) was 44.4%, with no instances of severe cGVHD observed (Figure 1B). No patient relapsed at the last follow-up on July 31, 2023. The estimated 1-year progression-free survival (PFS) and overall survival (OS) both stood at 90% (Figure 1C). Conclusion Short-term blinatumomab as a bridging therapy for adult patients with low-burden B-ALL transitioning to ASCT demonstrates comparable efficacy to standard dosing regarding disease control and survival outcomes.

Real World Outcomes in Patients with Ph-like ALL at the University of New Mexico

Introduction: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a heterogenous subtype of ALL characterized by different translocations and molecular mutations, resulting in a gene expression profile similar to Philadelphia chromosome positive (Ph+) ALL without an identified BCR::ABL1 translocation. Unfortunately, Ph-like ALL is characterized by worse response rates to conventional therapies and poor overall survival compared to other ALL subtypes. It is reported that 20-30% of patients with newly diagnosed ALL in the United States have Ph-like ALL and the incidence appears to vary according to ethnicity. While many therapies are under investigation including the addition of a tyrosine kinase inhibitor or ruxolitinib to conventional chemotherapy, a standardized and molecularly-based approach to treating patients with Ph-like ALL is not yet defined. There also remain questions about the efficacy of integrating inotuzumab ozogamicin or blinatumomab into first-line therapy for these patients. In addition, recent retrospective data has demonstrated promising effects of using traditional salvage therapies for ALL such as Car T cells, inotuzumab, or blinatumomab in patients with Ph-like ALL. However, the optimal sequence of treatment as well the efficacy of combining salvage therapies with agents such as ruxolitinib remains unknown. Herein, we present our institutional experience with diagnosing and treating adult patients with Ph-like ALL at the University of New Mexico. Our goal was to characterize the demographics, molecular and cytogenetic landscape, and treatment outcomes at a medical center that serves a patient population enriched for this disease. Methods: After IRB approval, we performed a retrospective chart review of patients diagnosed and treated at the University of New Mexico between January 1, 2018 and April 1, 2023. We included patients who were 18 years or older at the time of diagnosis, received first-line therapy at the University of New Mexico, and had gene expression profiling or FISH testing that was consistent with Ph-like ALL. Statistical analysis was performed using SPSS Statistics v.27 (IBM, 2020). Results: We identified 9 patients who met inclusion criteria. All 9 patients self-identified as either ‘American Indian or Alaska Native’ or ‘Hispanic or Latino.‘ The median age at diagnosis was 34 and the mean BMI at diagnosis was 34.6. 5 patients were CD20 positive and 1 patient had a concurrent IKZF1 mutation. All patients received induction chemotherapy with either a BFM regimen or HyperCVAD. 5 (55%) patients were refractory to induction and 6 (66%) patients eventually underwent allogeneic stem cell transplant as part of their treatment. 1 patient received Car T cell therapy with Brexucabtagene autoleucel following relapse after allogeneic stem cell transplant. 1 patient died 124 days after diagnosis and 8 patients are alive currently. 4 patients had IGH:: CRLF2, 2 patients had P2RY8::CRLF2,1 patient had GTF2I::PDGFRB,1 patient had IGH::BCL2,and one patient had both a positive low-dose array and a positive gene expression profile without an identified molecular or cytogenetic abnormality consistent with Ph-like ALL. Discussion: We present our preliminary experience of patients with Ph-like ALL diagnosed and treated at the University of New Mexico. Our patients were young with a median age of 34. Consistent with published data describing patients with Ph-like ALL, our patients had poor responses to traditional ALL treatments and most commonly had an identified fusion with CLRF2. Our data supports the urgent need for the development of further treatment options for patients with Ph-like ALL as well as clinical trials aimed at standardizing management.

Consolidation with Ponatinib Plus Sequential Blinatumomab and Chemotherapy after Low Intensity Dasatinib-Based Induction in Adults with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Outcomes from a Single Institution

Introduction: Dasatinib plus prednisone is a standard induction approach for adults with Philadelphia Chromosome positive (Ph+) ALL known to result in high remission rates with minimal toxicity, however optimal post-remission therapy has not been determined. Given the excellent outcomes observed in recent clinical studies using ponatinib in adult Ph+ ALL, we explored a strategy of switching the TKI to ponatinib and consolidating with sequential blinatumomab (blina) and chemotherapy after dasatinib + prednisone induction. In contrast to recent studies of blina + TKI wherein patients have received up to 3-5 cycles of blina, we limited the number of blina cycles to 2 to minimize cost and logistical burden. We also administered systemic chemotherapy after blina with the goal of decreasing risk of extramedullary relapse, which has been observed in studies of blina-based “chemotherapy-free” regimens. Methods: Since June 2021, all adult patients with Ph+ ALL (n=14) at our institution were switched to ponatinib (30mg/d then 15mg/d once complete molecular remission [CMR] achieved) after dasatinib + prednisone induction. Concurrent with TKI, patients could also receive blina for one or two cycles (at discretion of treating clinician), followed by up to four cycles of consolidative chemotherapy alternating between high-dose methotrexate (1.5g/m 2) and intermediate-dose cytarabine (1g/m 2 x 6 doses). Patients not proceeding to stem cell transplant continue ponatinib monotherapy for up to 5 years, and 12 doses of intrathecal methotrexate 15mg are given throughout the total course of treatment. Prior to June 2021, our institutional approach was to recommend allogeneic SCT in CR1 for all transplant candidates immediately after dasatinib + prednisone induction. We reviewed charts of patients with newly diagnosed Ph+ ALL at University of Colorado Hospital from 2014-2023 to compare outcomes of patients treated before 06/2021 (“dasatinib/SCT” cohort) and after 06/2021 (“ponatinib” cohort). Results: From 6/2021-02/2023, 14 patients (median age 54) with newly diagnosed Ph+ ALL were switched to ponatinib after dasatinib + prednisone induction. After induction, 12 patients received blina (median 1 cycle; range 1-2) and consolidation chemotherapy (median 4 cycles; range 3-4). Blina could not be obtained for 2 patients who instead received chemotherapy only for 6 cycles. 3 patients (21%) underwent allogeneic SCT in CR1 due to persistent detectable bcr/abl transcripts by qPCR, and all 3 continued ponatinib as maintenance after SCT. With a median follow-up of 15 months (range: 4-24 months) no relapses have occurred and all patients remain alive at last follow-up. No patients have discontinued ponatinib due to intolerance. Chemotherapy plus ponatinib was well-tolerated after blina, with all except for one patient having received all intended cycles (one patient stopped chemotherapy after 3 cycles due to excessive hematologic toxicity). Between 11/2014-03/2021, 36 patients (median age 50) with Ph+ ALL were treated with dasatinib + prednisone induction, after which 31 (86%) underwent allogeneic SCT in CR1. All non-transplant candidates continued TKI alone. With a median follow-up of 37 months (range: 4-102 months), 11 relapses have occurred, 9 of which occurred after SCT. Among 13 patients who died during follow-up, 7 deaths were due to relapsed/refractory ALL and 6 were due to treatment-related mortality. Comparing outcomes between the two cohorts, relapse-free survival is improved in the more recent (ponatinib) cohort compared to the earlier (dasatinib/SCT) cohort (p=0.044, log-rank test) (Figure 1) despite a lower rate of allogeneic SCT in CR1 (21% vs 86%). No difference in overall survival (p=0.12) has been observed (not shown). Conclusions: For adults with Ph+ ALL, switching to ponatinib after dasatinib-based induction and consolidating with blina and chemotherapy is a safe and potentially effective strategy. The optimal number of blina cycles given post-remission is unclear, though we observed favorable outcomes in patients receiving a median of only 1 cycle, and maximum of 2 cycles. Favorable outcomes despite the low rate of allogeneic SCT (21%) seen in our cohort suggest that SCT may be safely avoided for some patients who receive ponatinib plus blina and chemotherapy-based consolidation.

Outcomes of Patients with B-ALL with Concomitant BCR::ABL1 and CRLF2 Rearrangements

Background: Outcomes of patients with Philadelphia chromosome positive (Ph+) ALL have improved significantly with the introduction of tyrosine kinase inhibitors (TKI). Ph-like ALL is a high-risk subtype of B-ALL with gene expression profile similar to Ph+ ALL, but without the BCR-ABL translocation. About 50% of the patients with Ph-like ALL have CRLF2 rearrangement (CRLF2-R) and are associated with poor outcomes with conventional chemoimmunotherapy. The co-occurrence of both Ph+ and CRLF2-R is rare (Jain, Haematologica 2017) and long-term outcomes unknown. Methods: We retrospectively analyzed the Leukemia and Pathology databases for patients who presented to the MD Anderson Cancer Center (MDACC) and were noted to have concomitant Ph+ and CRLF2-R. Ph+ was assessed by conventional cytogenetics / FISH / PCR for BCR-ABL1. CRLF2-R was assessed by flow cytometry / FISH. Outcomes assessed were best response (complete remission (CR), relapse, minimal residual disease (MRD), event-free survival (EFS) and overall survival (OS). Results: We identified 8 patients (5 newly diagnosed and 3 R/R B-ALL) who had concurrent Ph+ and CRLF2-R rearrangement (Table 1). The median age was 29 (range, 14-57), 6 (75%) were of Hispanic ethnicity, and 6 (75%) were men. The median clone size of CRLF2-R and Ph+ were 73% (56-92%) and 52% (4-96%), respectively. The most frequent mutated gene was JAK2 in 3/8 (38%) patients. All patients were treated with chemoimmunotherapy or immunotherapy + TKI (ponatinib, n=7; dasatinib, n=1). The median follow-up was 23 months. The best response achieved was CR in 6/8 (75%). The median EFS was 8.6 months; 12-month OS was 75% (Figure 1). A total of 3/6 (50%) responders had a subsequent relapse with 2/3 relapses occurring in the extramedullary compartment (one in central nervous system and one intraperitoneal); both with CRLF2-R clone without Ph+. Of the 5 patients who presented to MDACC as newly diagnosed B-ALL, two were treated with frontline with Hyper-CVAD + ponatinib/dasatinib, two with blinatumomab + ponatinib and the one with a pediatric regimen + dasatinib. Best response was CR with negative MRD in 5/5 (100%). All 5 patients cleared both rearrangements (Ph+ and CRLF2) at the time of remission; 2/5 patients showed CRLF2-R during relapse (without the Ph+). The 12-month OS and EFS were 80% and 60%, respectively. Three patients presented to MDACC with R/R B-ALL. They received HCVAD + ponatinib/dasatinib +/-ruxolitinib. Best response was CR in 1/3 (33%) patients. All 3 patients cleared Ph+, but CRLF2-R persisted in 2 patients. Conclusions: Patients who harbor concomitant Ph+ and CRLF2-R represent a rare but high-risk subgroup of B-ALL. High rate of relapse was noted despite treatment with chemotherapy + TKI +/- ruxolitinib; several patients cleared the Ph+ clone, but CRLF2-R clone persisted suggesting novel interventions against CRLF2-R B-ALL are warranted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Dermatologic Adverse Events in Acute Lymphocytic Leukemia Patients Treated with Bispecific T-Cell Engager Blinatumomab

Blinatumomab is a novel FDA-approved bi-specific T-cell engager (BiTE) that significantly improves survival (vs standard chemotherapy) in adults with relapsed or refractory Philadelphia chromosome positive or negative B-cell precursor ALL (B-ALL) and is associated with high rates of clearing persistent measurable residual disease. Though the best known adverse effects associated with blinatumomab include cytokine release syndrome and neurologic toxicity, dermatologic adverse events (DAE) have also been reported in 16% of patients in clinical trials (FDA, 2018). In this study, we aimed to assess the incidence of DAEs in B-ALL patients treated with blinatumomab and characterize their associated clinical and histopathologic features. We conducted a retrospective analysis of B-ALL patients treated with blinatumomab monotherapy at Memorial Sloan Kettering Cancer Center from 1/1/2012 - 10/1/2021 (N=45). Seven patients experienced a total of nine DAEs (15.6%). Median number of blinatumomab cycles at time of DAE onset was one (range cycles 1-3). Median time to DAE onset following blinatumomab induction was 40 days (range 5-115 days). The most common DAEs were rashes (N=4); types included eczema, folliculitis, papular dermatitis, and panniculitis. Other DAEs (N=5) included new onset psoriasis, seborrheic dermatitis, acne, facial erythema, and nail dystrophy. All DAEs were grade 1, many DAEs did not require treatment, and no DAEs warranted interruption or discontinuation of blinatumomab. Four of the 7 patients with DAEs developed CRS at any point during blinatumomab therapy (ASTCT consensus grade 1, N=3; grade 2, N=1). Six of 7 patients with DAE achieved undetectable minimal residual disease (MRD) in the course of blinatumomab therapy or maintained MRD negativity. This is the most comprehensive study to report incidence and clinico-morphologic patterns of DAEs associated with blinatumomab monotherapy. Blinatumomab DAEs may be more common in patients who experience CRS; this finding may support that DAEs are the result of increased circulating cytokines secondary to effective immune activation by blinatumomab. DAEs are mild and we recommend that patients with severe rash during blinatumomab infusion are carefully evaluated for other etiologies of rash.

AML-173 Pseudotumor Cerebri (PTC) in Patients With Acute Leukemia (AL)

Pseudotumor cerebri (PTC) is characterized by headache, vision changes, and fundus papilledema. Primary PTC is often seen in obese women (childbearing age) and secondary with medications such as all-trans retinoic acid (ATRA). We analyze clinical presentation, and outcomes of PTC in patients with acute leukemia (AL) treated at a general hospital. Single-center retrospective study. We reviewed cases of AL patients with PTC at Memorial Hermann Hospital, Texas Medical Center between January 2013 and April 2022. Three (2.3%) of 127 patients (AML=85, APL=29, ALL= 13) had PTC. Fit non-APL patients received induction chemotherapy (IC) with purine analogs-cytarabine-anthracycline. Unfit patients received a hypomethylating agent and venetoclax. APL patients received IC with arsenic trioxide and ATRA. Patients suspected of having APL were started on ATRA, and discontinued with a negative PML-RARA FISH test. We describe the incidence, risk factors, clinical presentation, and outcomes of AL patients with PTC. Mean age was 42 years. Mean BMI was 42. All were white women. Two had AML, and one Philadelphia chromosome-positive ALL. AML patients received 3 doses of ATRA discontinued after negative PML-RARA FISH. One AML patient had PTC at presentation. The other developed PTC 3 months later. One AML patient had PTC 30 years before being treated for 6 months with acetazolamide; PTC recurred 3 months after her diagnosis. All patients had headaches, blurry vision, and papilledema with brain MRI showing optic sheath distension, globe flattening, and papilla cupping, all features suggestive of PTC. In two, the opening lumbar puncture pressures were elevated at 30 and 35 cm H2O. Cerebrospinal fluid cytology and flow cytometry were negative for leukemia. Two patients (AML=1, ALL=1) received intrathecal (IT) chemotherapy for CNS prophylaxis. All patient's symptoms improved with acetazolamide. LP done for IT chemotherapy helped to alleviate symptoms. No patient with APL (29 patients) developed PTC during treatment with ATRA. PTC is a rare diagnosis that can complicate the clinical course of AL patients. In addition to ATRA-induced PTC, clinicians should consider primary PTC, seen most often in morbidly obese women of childbearing age.

Retrospective analysis of healthcare disparities in Philadelphia chromosome-positive ALL: A single-institution experience of a large metropolitan area.

12067 Background: Philadelphia chromosome-positive (Ph+) ALL is an aggressive hematological neoplasm with a dismal prognosis. Hematopoietic stem cell transplant (HSCT) remains the standard of care for those reaching complete remission due to high relapse rates with conventional therapy alone. We have previously demonstrated findings concerning for imbalanced outcomes among racial groups in AML. In the era of TKIs targeting BCR-ABL1 in combination with conventional therapy, it is unclear whether trends noted in AML are also seen in Ph+ ALL. Thus, the purpose of this study was to investigate the impact of healthcare disparities on outcomes in Ph+ ALL with regards to access to care, response rates, toxicities, and overall outcomes. Methods: We retrospectively analyzed 59 patients with Ph+ B-ALL treated at our institution with TKIs +/- chemoimmunotherapy during January 2015 to January 2021. Baseline patient demographics were obtained, including insurance type, performance status at diagnosis, cytogenetic and molecular profiling, dates and doses of induction, toxicity, response, MRD analysis, and HSCT access and outcomes. Race was determined by patient self-report as recorded in the electronic medical record. Results: We divided 58 patients (one excluded as race was unknown) into two cohorts: 23 (39.7%) patients that identified as minorities, including African American, Hispanic/Latino, and Asian, and 35 (60.3%) identifying as White. There were no differences in baseline characteristics including age (p =.367), sex (p =.788), ECOG at diagnosis (p =.438), Charlson Comorbidity Index scores (p =.551), or presence of additional poor-prognostic mutations (p &gt;.999). Despite this, minorities were significantly more likely to be treated with lower-intensity regimens compared to non-minorities (p =.022). Achievement of CR by MRD was approaching statistical significance favoring the non-minority cohort (60.0% versus 27.3%, p =.055). Receipt of HSCT numerically favored the non-minority cohort, approaching statistical significance (54.3% versus 26.1%, p =.056). At a median follow-up time of 3.3 y., the median OS was not reached between the two groups and there was no difference in survival between the two groups (p =.662). Conclusions: Despite similar patient-related characteristics, minority populations are more likely to be treated with lower-intensity strategies, concerning for bias in regimen selection. Achievement of CR by MRD and receipt of HSCT appeared to be numerically lower in the minority cohort. While there appeared to be no difference between the two cohorts with regards to survival during the follow-up period, it is unclear if this would be maintained with longer follow-up. These findings highlight the need for ongoing vigilance regarding physician biases and increasing the need for improving access to curative treatment for all patients.

Analysis of real-world outcomes of IKZFmut in Philadelphia chromosome-positive ALL: A retrospective, single-institution experience.

e19032 Background: Presence of the Philadelphia chromosome (Ph+) or IKZFmut is associated with a poor prognosis in B-cell ALL. The clinical impact of both mutations occurring together in adult patients is currently unknown. We sought to analyze outcomes of patients with Ph+ B-ALL and IKZFmut treated with induction with TKI-based regimens outside of the context of clinical trials. Methods: We identified 10 patients with Ph+ B-ALL treated at our institution during January 2015 to January 2021 that had IKFZmut identified through NGS. Seven had IKFZmut at the time of diagnosis and three acquired IKFZmut at the time of relapse. Baseline patient demographics were obtained, including age, performance status and comorbidities at diagnosis, cytogenetic and molecular profiling through NGS, doses of induction, toxicity, response, measurable residual disease (MRD) analysis, and survival, and incidence of relapse. The event for calculating the overall survival (OS) was the date of death and patients were otherwise censored at the date of last contact. Results: The median age of the 7 patients IKFZmut with at diagnosis was 58 years (range: 44 - 72), 57.1% were male, the median ECOG score was 1 (range: 1 - 3), and the median Charlson Comorbidity Index score was 4. Other commonly occurring mutations were ABL1 (42.9%), with CDKN2A, ETV6, and PTPN11 occurring at 14.3% each. Dasatinib was the most common TKI given in 85.7% of patients in combination with hyperCVAD (42.9%), EWALL-Ph-01 (28.6%), ECOG 1910 (14.3%), and ECOG 2993 (14.3%). In total, 71.4% achieved CR, with 50.0% in CR by MRD. Two patients received allogeneic stem cell transplant (HSCT) and 28.6% had relapsed or refractory disease by 1.2 years. At a median follow-up time of 1.7 years, the median survival was not reached. Three additional patients were found to have IKZFmut at the time of relapse or refractory disease. The median age was 38 years, 2 (66.6%) had a co-occurring mutation in ABL1, and all were treated with dasatinib at time of salvage, two in combination with hyperCVAD and one with EWALL-Ph-01. There were no deaths during induction and two patients had evaluable responses and both achieved CR, and one by MRD. Conclusions: To the best of our knowledge, these are among the first of limited reports regarding outcomes of adult patients with Ph+ B-ALL and IKZFmut. Although the cohort is limited by sample size due to the rarity of the co-occurring mutations, the response rates appear to be numerically similar in upfront treatment of Ph+ and IKZFmut compared to historical data for Ph+ B-ALL alone in the era of TKIs. Gain of IKZFmut may be a sign of clonal evolution of disease, and further work to elucidate prognostic implications in the relapsed and refractory group is warranted. Larger prospective, randomized studies investigating differential responses to modern combinatorial chemoimmunotherapy + TKI approaches are warranted in this population.

Efficacy and safety of high-intensity versus reduced-intensity induction in Philadelphia chromosome-positive all ineligible for HSCT.

e19031 Background: Treatment options for Philadelphia chromosome-positive (Ph+) ALL are increasing. When combined with TKIs, it is unclear if high-intensity regimens lead to a survival benefit compared to reduced-intensity regimens in patients that are not candidates for allogenic hematopoietic stem cell transplant (HSCT). In this study, we sought to examine outcomes of high-intensity and reduced-intensity induction regimens and concurrent TKI administration with respect to toxicity, response, and survival in non-transplant candidates. Methods: We retrospectively analyzed 31 patients with Ph+ B-ALL treated at our institution during January 2015 to January 2021 that were not candidates for HSCT. Baseline patient demographics were obtained, including age, performance status at diagnosis, cytogenetic and molecular profiling through NGS, doses of induction, toxicity, response, MRD analysis, and survival. The event for calculating the overall survival (OS) was the date of death and patients were otherwise censored at the date of last contact. Results: We divided the cohort of 31 patients into two sub-cohorts: a high-intensity cohort of 22 patients treated with TKIs and hyperCVAD, CALGB 10403, or ECOG 1910 and a low-intensity cohort of 9 patients treated with TKI + steroids + vincristine, TKI + steroids, or TKI alone. There was expectedly a significant difference in age between the two groups (p = .002) with more advanced age in the reduced-intensity cohort, though no difference in sex (p≥.999), ECOG score at diagnosis (p = .886), or Charlson Comorbidity Index score (p = .180). Grade 3 or higher toxicity was approaching statistical significance with more toxicity in the higher-intensity group (p = .075). With fewer deaths during induction, achievement of CR or CRi was higher in the reduced-intensity cohort (100% versus 73.7%), though was not significantly different between the groups (p = .288) and the median OS was not reached in either cohort (p = .935) after a median follow-up time of 3.29 years. Conclusions: Acknowledging the limits of a small sample size and retrospective nature of the study, there was no observed difference in survival between high-intensity and reduced-intensity induction with TKIs for patients ineligible for HSCT. Reduced-intensity inductions were associated with a trend toward less severe toxicity. These findings are suggestive that reduced-intensity induction with TKIs in Ph+ ALL may represent a reasonable option for those ineligible for HSCT. Prospective randomized controlled trials in this population are warranted.

Genome-Wide CRISPR-Cas9 Screen Identifies Rationally Designed Combination Therapies Relevant for CRLF2-Rearranged Ph-like ALL

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL, also known as BCR-ABL1-like ALL) is a disease entity of B-cell ALL that exhibits a gene expression profile, similar to that of Philadelphia chromosome-positive ALL. Ph-like ALL is categorized into two disease subtypes: “ABL-class”- and “CRLF2/JAK pathway”-types, both of which harbor gene alterations that constitutively activate cytokine/growth factor-related signals. Ph-like ALL with the CRLF2 rearrangement exhibits poor clinical outcomes and is the most common subtype of Ph-like ALL. Tyrosine kinase inhibitor (TKI)-based treatment regimens are effective in treating ABL-class type Ph-like ALL; however, no standard regimen has been established for the CRLF2/JAK pathway type. While multiple chemotherapeutic regimens, including Ruxolitinib monotherapy and/or its combination with chemotherapy, are being tested, their efficacy is reportedly limited. Thus, novel approaches are needed to treat CRLF2/JAK pathway type Ph-like ALL, in particular for CRLF2-rearranged (CRLF2-r) ALL.To identify molecules/pathways relevant for CRLF2-r ALL pathogenesis, we performed genome-wide CRISPR-Cas9 dropout screens in the presence or absence of Ruxolitinib using two IgH-CRLF2-r ALL lines (MUTZ5 and KOPN49) that differ in RAS mutational status. To do so, we employed a baboon envelope pseudotyped lentiviral vector system, which, for the first time, enabled highly efficient transduction of human B cell amenable for genome-wide CRSPR/Cas9 screens.While sgRNAs targeting CRLF2, IL7RA or JAK1/2 significantly affected cell fitness in both lines, those targeting STAT5A, STAT5B or STAT3 did not, suggesting that the JAK-STAT axis is largely dispensable for IgH-CRLF2-r ALL cell survival. We show that regulators of RAS signaling are critical for cell fitness and Ruxolitinib sensitivity and that CRKL and FLT3 depletion enhances Ruxolitinib sensitivity in RAS wild-type (WT) cells. Gilteritinib, a pan-tyrosine kinase inhibitor that reduces CRKL activity, effectively killed RAS WT IgH-CRLF2-r ALL cells in vitro and in vivo, either alone or combined with Ruxolitinib. We further show that combining Gilteritinib with Trametinib, a MEK1/2 inhibitor, is an effective means to target IgH-CRLF2-r ALL cells regardless of RAS mutational status.Our study delineates molecules/pathways relevant for CRLF2-r ALL pathogenesis and could suggest rationally designed combination therapies appropriate for disease subtypes. DisclosuresNo relevant conflicts of interest to declare.

Genomic and Outcome Analyses of Philadelphia Chromosome-like (Ph-like) NCI Standard Risk B-Acute Lymphoblastic Leukemia (SR B-ALL) Patients Treated on Children's Oncology Group (COG) AALL0331

Introduction: Ph-like ALL is defined by a gene expression profile similar to Philadelphia chromosome-positive ALL but lacking the BCR - ABL1 fusion. Ph-like ALL is comprised of diverse genomic alterations activating kinase and cytokine receptor signaling, including chimeric fusions involving ABL1 and related genes (ABL2, CSF1R, PDGFRB ; ABL-class fusions), genomic rearrangements leading to CRLF2 over-expression, JAK2 gene fusions, and truncating rearrangements of EPOR . We have published several large studies describing the clinical features, treatment outcome, and genomic alterations in Ph-like ALL that focused on patients with NCI high risk (HR) ALL (age ≥10 years or WBC ≥50,000) or those with SR ALL (age 1-9.99 years and WBC <50,000) and elevated minimal residual disease (MRD) at the end of induction (EOI; Reshmi, BLOOD 2017 and Roberts, NEJM 2014). The purpose of the current study was to assess the frequency of genomic lesions in Ph-like SR ALL patients lacking HR features.Methods: We retrospectively analyzed 1023 unselected newly-diagnosed SR ALL patients enrolled on COG AALL0331 between 2006 and 2008, and compared characteristics of SR Ph-like cases to the HR patients described in our prior studies. All cases were screened using an 8-gene Taqman low-density array (LDA) PCR assay to identify the Ph-like GEP (Harvey, ASH 2013). Ph-like cases with elevated CRLF2 expression were tested for CRLF2 rearrangement (CRLF2 -R; P2RY8 - CRLF2 by Taqman PCR on the LDA card and IGH - CRLF2 by FISH). JAK mutations in CRLF2 -R cases were tested by Sanger sequencing. Ph-like cases without CRLF2 -R were tested for previously identified kinase fusions involving ABL1, ABL2, CSF1R, JAK2, NTRK3, and PDGFRB by RT-PCR. A subset of Ph-like cases without detected genomic alterations underwent RNA-sequencing using standard Illumina library preparation.Results: A total of 205 patients had LDA value ≥0.5, with 145 (14.2%) remaining after exclusion of BCR-ABL1 and ETV6-RUNX1 . Of these 145, 85 were CRLF2high (57.9%) as defined by CRLF2 expression levels on the LDA card. Among these 85, 42 (50%) had CRLF2 -R, compared to 80% in HR patients. P2RY8 - CRLF2 was seen in 36 cases, IGH - CRLF2 in 4 and 2 had CRLF2 -R with an unknown partner; 14 (32.6%) of these had a concomitant JAK mutation. Of the 60 Ph-like CRLF2low cases, five had a targetable kinase fusion identified by RT-PCR or RNA sequencing: two ABL - class fusions (ZMIZ1 - ABL1, EBF1-PDGFRB); one PAX5-JAK2 fusion; one ETV6-JAK2 fusion; and one ETV6 - NTRK3 fusion. The 145 Ph-like cases had inferior 7-year event-free survival (EFS; 83.1±3.5% vs. 90.6 ±0.1%; P=0.005) and non-significantly inferior 7-year overall survival (OS; 93.5±2.3% vs. 95.5 ±0.8%; P=0.184) compared to 869 non Ph-like cases. Ph-like ALL cases were more likely to have end induction MRD ≥ 0.01% (24.3% vs. 17.9%; P=0.049), and positive MRD was predictive of outcome for Ph-like (7-year EFS: 73.2±8.3%, vs. 86.6 ±3.7%; P=0.079; 7-year OS: 88.2 ±5.9% vs. 95.9±2.1%; P=0.162) and non Ph-like patients (7-year EFS: 79.7 ±3.7% vs. 93.3 ±1.0%; P <0.0001; 7-year OS: 90.2% SE 2.7 vs. 97.4±0.9%; P <0.0001). In multivariate analyses, Ph-like and MRD status EOI were significant predictors of EFS (p=0.016; <0.0001 respectively), while only MRD had a significant impact on OS.Conclusion: Ph-like ALL is less common in NCI SR than HR patients with significant differences in the frequency of various genomic alterations in Ph-like ALL cases based on NCI risk group. Our previous studies have shown that Ph-like ALL HR patients have a substantially increased risk of treatment failure and death as compared to non Ph-like HR patients (Mullighan, NEJM 2009 and Roberts, NEJM 2014). This cohort of SR Ph-like patients had a significantly inferior EFS and a trend to inferior OS, but the magnitude of effect was much smaller than that seen in HR Ph-like patients, with overall outcomes much better in SR as compared to HR Ph-like patients. These findings underscore the significant differences in Ph-like ALL frequency, genetic subtypes, and outcome based on age and initial WBC. [Display omitted] DisclosuresBorowitz:Beckman Coulter: Honoraria; Becton-Dickinson Biosciences: Research Funding; HTG Molecular: Honoraria. Zweidler-McKay:ImmunoGen: Employment. Mattano:HARP Pharma Consulting, LLC: Employment. Mullighan:Loxo Oncology: Research Funding; Amgen: Consultancy. Hunger:Amgen: Consultancy, Equity Ownership; Novartis: Consultancy; Erytech Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Honoraria.

Effect of Postreinduction Therapy Consolidation With Blinatumomab vs Chemotherapy on Disease-Free Survival in Children, Adolescents, and Young Adults With First Relapse of B-Cell Acute Lymphoblastic Leukemia

Standard chemotherapy for first relapse of B-cell acute lymphoblastic leukemia (B-ALL) in children, adolescents, and young adults is associated with high rates of severe toxicities, subsequent relapse, and death, especially for patients with early relapse (high risk) or late relapse with residual disease after reinduction chemotherapy (intermediate risk). Blinatumomab, a bispecific CD3 to CD19 T cell-engaging antibody construct, is efficacious in relapsed/refractory B-ALL and has a favorable toxicity profile. To determine whether substituting blinatumomab for intensive chemotherapy in consolidation therapy would improve survival in children, adolescents, and young adults with high- and intermediate-risk first relapse of B-ALL. This trial was a randomized phase 3 clinical trial conducted by the Children's Oncology Group at 155 hospitals in the US, Canada, Australia, and New Zealand with enrollment from December 2014 to September 2019 and follow-up until September 30, 2020. Eligible patients included those aged 1 to 30 years with B-ALL first relapse, excluding those with Down syndrome, Philadelphia chromosome-positive ALL, prior hematopoietic stem cell transplant, or prior blinatumomab treatment (n = 669). All patients received a 4-week reinduction chemotherapy course, followed by randomized assignment to receive 2 cycles of blinatumomab (n = 105) or 2 cycles of multiagent chemotherapy (n = 103), each followed by transplant. The primary end point was disease-free survival and the secondary end point was overall survival, both from the time of randomization. The threshold for statistical significance was set at a 1-sided P <.025. Among 208 randomized patients (median age, 9 years; 97 [47%] females), 118 (57%) completed the randomized therapy. Randomization was terminated at the recommendation of the data and safety monitoring committee without meeting stopping rules for efficacy or futility; at that point, 80 of 131 planned events occurred. With 2.9 years of median follow-up, 2-year disease-free survival was 54.4% for the blinatumomab group vs 39.0% for the chemotherapy group (hazard ratio for disease progression or mortality, 0.70 [95% CI, 0.47-1.03]); 1-sided P = .03). Two-year overall survival was 71.3% for the blinatumomab group vs 58.4% for the chemotherapy group (hazard ratio for mortality, 0.62 [95% CI, 0.39-0.98]; 1-sided P = .02). Rates of notable serious adverse events included infection (15%), febrile neutropenia (5%), sepsis (2%), and mucositis (1%) for the blinatumomab group and infection (65%), febrile neutropenia (58%), sepsis (27%), and mucositis (28%) for the chemotherapy group. Among children, adolescents, and young adults with high- and intermediate-risk first relapse of B-ALL, postreinduction treatment with blinatumomab compared with chemotherapy, followed by transplant, did not result in a statistically significant difference in disease-free survival. However, study interpretation is limited by early termination with possible underpowering for the primary end point. ClinicalTrials.gov Identifier: NCT02101853.

Comparison of prognostic significance between multiparameter flow cytometry and real-time quantitative polymerase chain reaction in the detection of minimal residual disease of Philadelphia chromosome-positive acute B lymphocytic leukemia before allogeneic hematopoietic stem cell transplantation

目的探讨多参数流式细胞术（MFC）与实时定量聚合酶链反应技术（RQ-PCR）两种方法检测费城染色体阳性（Ph+）急性B淋巴细胞白血病（B-ALL）患者异基因造血干细胞移植（allo-HSCT）前微小残留病（MRD）的预后意义。方法回顾性分析2014年7月至2018年2月在北京大学血液病研究所接受allo-HSCT的280例Ph+ B-ALL患者，同时用MFC和RQ-PCR法（检测BCR-ABL融合基因表达）检测移植前MRD。结果RQ-PCR与MFC检测MRD具有相关性（rs＝0.435，P<0.001）。MFC、RQ-PCR法检测移植前MRD的阳性率分别为25.7％（72/280）、60.7％（170/280）。移植前MFC-MRD阳性组患者移植后白血病3年累积复发率（CIR）明显高于MFC-MRD阴性组（23.6％对8.6％，P<0.001）。RQ-PCR检测BCR/ABL融合基因阳性组（RQ-PCR MRD阳性组）的3年CIR、非复发死亡（NRM）、无白血病生存（LFS）、总生存（OS）与BCR/ABL融合基因阴性组（RQ-PCR MRD阴性组）相比差异均无统计学意义（P>0.05）。移植前RQ-PCR MRD≥1％组比<1％组具有更高的3年CIR（23.1％对11.4％，P＝0.032）、更低的LFS率（53.8％对74.4％，P＝0.015）与OS率（57.7％对79.1％，P＝0.009）。多因素分析显示，移植前MFC-MRD阳性是影响移植后CIR的危险因素（HR＝2.488，95％CI1.216～5.088，P＝0.013），移植前RQ-PCR MRD≥1％是影响LFS（HR＝2.272，95％CI 1.225～4.215，P<0.001）、OS（HR＝2.472，95％ CI 1.289～4.739，P＝0.006）的危险因素。MFC检测MRD预测复发的敏感性、特异性、阳性预测值（PPV）、阴性预测值（NPV）分别为48.50％、77.56％、23.62％、87.16％。以RQ-PCR MRD≥1％预测复发的敏感性、特异性、PPV、NPV分别为23.00％、88.59％、17.15％、91.84％。移植前MFC-MRD阳性或RQ-PCR MRD≥1％二者任一成立为指标预测移植后复发的敏感性、特异性、PPV、NPV分别为54.29％、73.88％、45.70％、91.87％。结论MFC和RQ-PCR法检测移植前MRD水平均可预测Ph+ B-ALL患者移植预后。移植前MFC-MRD阳性是移植后复发的危险因素。联合使用两种方法（移植前MFC-MRD阳性状态或RQ-PCR MRD≥1％成立）可提高预测移植后复发的敏感性、阳性预测值与阴性预测值，有助于更好筛选出高危患者。

159 - Dasatinib Prednisone Is an Effective Induction Strategy Prior to Transplant for Philadelphia Chromosome Positive ALL

159 - Dasatinib Prednisone Is an Effective Induction Strategy Prior to Transplant for Philadelphia Chromosome Positive ALL

Genetics and Diagnostic Approach to Lymphoblastic Leukemia/Lymphoma.

Our understanding of the genetics and biology of lymphoblastic leukemia/lymphoma (acute lymphoblastic leukemia, ALL) has advanced rapidly in the past decade with advances in sequencing and other molecular techniques. Besides recurrent chromosomal abnormalities detected by karyotyping or fluorescence in situ hybridization, these leukemias/lymphomas are characterized by a variety of mutations, gene rearrangements as well as copy number alterations. This is particularly true in the case of Philadelphia-like (Ph-like) ALL, a major subset which has the same gene expression signature as Philadelphia chromosome-positive ALL but lacks BCR-ABL1 translocation. Ph-like ALL is associated with a worse prognosis and hence its detection is critical. However, techniques to detect this entity are complex and are not widely available. This chapter discusses various subsets of ALL and describes our approach to the accurate classification and prognostication of these cases.