Liedtke, Michaela

Introduction E1910 randomized pts with ALL aged 30-70 years who were measurable residual disease negative (MRD-) by multi-color flow cytometry (FC) after intensification to conventional chemotherapy (chemo) with or without blinatumomab (blina). The addition of blina resulted in improved overall survival (OS) (Litzow, NEJM 2024) and led to a new standard of care. Older ALL pts have inferior outcomes when compared to younger pts in part due to increased treatment toxicity. In E1910, exposure to dexamethasone and pegasparagase was reduced for older pts (age >55 years). We present results of subgroup analyses describing outcomes of older pts enrolled in E1910. Methods Details of the E1910 protocol remission induction (step 1), high dose methotrexate with pegaspargase intensification (step 2), blina randomization (step 3), and maintenance (step 4) or allogeneic hematopoietic stem cell transplant (HCT) were previously presented (Litzow, NEJM 2024). MRD status was determined after step 2 centrally with 6-color FC with MRD- defined as <0.01% in the bone marrow (BM). Following approval of blina in the US for MRD positive (MRD+) disease in 2018, MRD+ pts were assigned to the blina arm and no longer randomized. The primary objective was to compare the OS and relapse free survival (RFS) among older pts aged >55 years (pre-specified stratification factor) who received chemo + blina to that of pts who received chemo alone (step 3 treatment). Estimates of OS and RFS were calculated using the Kaplan-Meier method. Comparison of OS and RFS between treatment arms was conducted using the two-sided stratified log-rank test and Cox model with CD20 status, rituximab use, and whether pts intended to receive HCT or not as stratification factors. Stratified Multivariate Cox models of OS and RFS were used to further evaluate the effect of step 3 treatment, adjusted by gender, white blood cell count (WBC), platelets, hemoglobin, peripheral blood blasts, BM blasts, performance status and combined molecular risk category. Results Among the 488 enrolled pts, 211 were ≥55 years old with median age of 61 (range 55-70). Among older pts, 49.3% were female and 83.4% were white, 17 (8.1%) pts had WBC >30.000/uL at the time of diagnosis. 156 (73.9%) pts had CD10+ early B-ALL and 46 (21.8%) had CD10- B-ALL immunophenotype. The most common genetic subgroups were low hypodiploid (n=58, 27.5%), BCR::ABL1-like (n=34, 16.1%) and KMT2A rearranged (n=26, 12.3%). 8.1% of pts had low, 9.0% intermediate, 63.5% high combined molecular risk disease and in 19.4% of pts risk could not be assigned. Baseline characteristics were not significantly different in chemo + blina and chemo only pts. The median follow-up for this analysis from step 1 registration was 54.6 months. Complete response with (CR) or without (CRi) count recovery after induction was observed in 174 (82.5%) pts (167 CR, 7 CRi). 93 (44%) pts were MRD-. 32 (15.1%) pts received HCT on study and 24 (11.4%) pts received it off study. Among MRD- pts (n=93), 46 were randomized to and 45 received blina: 6 (13.3%) pts had 1, 14 (31.1%) had 2, 2 (4.4%) had 3 and 23 (51.1%) had 4 cycles. 3-year OS were 71% and 67% for the blina and the chemo only arm (univariate model: HR 0.75, 95% CI: 0.37-1.50; multivariate model: HR 0.56, 95% CI: 0.25-1.27). 3-year RFS were 69% and 59% for the blina and the chemo only arm (univariate model: HR 0.75, 95% CI: 0.39-1.45; multivariate model: HR 0.67, 95% CI: 0.32-1.42). Among MRD+ pts (n=25), 14 were randomized to and 11 received blina: 7 (63.6%) pts had 2, and 4 (36.4%) had 4 cycles. 3-year OS were 66% and 44% for the blina vs the chemo only arm (univariate model: HR 0.66, 95% CI: 0.12-3.64). 3-year RFS were 64% and 31% for the blina vs the chemo only arm (univariate model: HR 0.64, 95% CI: 0.15-2.74). Frequency of treatment-related toxicities among older pts during different study phases and treatment assignments will be presented. Conclusion Despite evidence of improved outcomes in the whole study cohort, the addition of blina to consolidation chemo for older pts with ALL was not associated with statistically significant improvement of OS or RFS in this exploratory analysis not powered to detect the difference in subgroups. This is possibly due to sample size but may be due to biologic differences in the older adult population. Further studies are needed to definitively determine tolerance and benefit of blina addition to consolidation for older pts with ALL.

Background: Patients with acute lymphoblastic leukemia (ALL) receiving L-asparaginase (ASP) based induction therapy have a high risk of venous thromboembolism (VTE). Studies investigating universal thromboprophylaxis strategies have yielded sub-optimal results. Risk prediction models are needed to identify high-risk patients who would be candidates for intensification of thromboprophylaxis, and lower risk patients who are unlikely to benefit. Aims: Derive and externally validate a risk prediction model for VTE in patients with ALL receiving ASP therapy. Methods: We conducted a multicenter, international, cohort study of patients with newly-diagnosed ALL receiving ASP-based induction therapy (≥18yrs). The derivation and external validation cohorts included 306 and 97 patients without VTE prior to ASP therapy, respectively. Patients on therapeutic anticoagulation at index were excluded. Patients were followed from date of first ASP dose for 100 days post ALL diagnosis or until VTE, therapeutic anticoagulation or death. Candidate predictors were documented at ALL diagnosis and included demographics, disease and treatment characteristics, VTE history, comorbidities, thromboprophylaxis, complete blood count, fibrinogen and d-dimer. D-dimer was only analyzed within the 7 derivation cohort centers who routinely tested this at ALL diagnosis with <20% missing values. Primary outcome was VTE at any site (centrally confirmed). Secondary outcomes included major bleeding by ISTH criteria. Cause-specific Cox proportional hazard regression was performed to identify VTE risk factors in the derivation cohort while treating death as a competing event. Variables with p-value <0.1 on univariable analysis were included in a multivariable model and subsequently used in the risk model if p-value <0.05. Lastly, the derived VTE risk prediction model was tested in the external validation cohort for association with time to VTE using cause-specific Cox proportional hazard model. All analyses were stratified by center and use of low molecular weight heparin prophylaxis (at any dose on the date of first ASP dose). Results: The cumulative incidence of VTE in the derivation cohort was 17% at 30 days (95% confidence interval [CI] 13% - 21%) and 22% at 90 days (95% CI 17% - 27%). The multivariable model included hyperlipidemia (hazard ratio [HR] 1.35; 95% CI 0.56 - 3.27), body mass index ≥ 25 kg/m² (HR 1.49; 95% CI 0.75 - 2.95), platelet count ≥ 25 x 10⁹/L (HR 1.42; 95% CI 0.67 - 3.00), increasing hemoglobin per 1 g/dL (HR 1.17; 95% CI 1.03 - 1.32) and d-dimer ≥ 1 µg FEU/mL (HR 2.68; 95% CI 1.08 - 6.66). Hemoglobin as a continuous variable and d-dimer ≥ 1 µg FEU/mL were included in the final model and used to create a risk score which was weighted by estimated log-HR sum of these risk factors. The lowest risk quartile (risk score below 2.1) successfully differentiated between a lower 30-day cumulative VTE incidence (4%, 95% CI 0.72% - 12%) compared with the other quartiles (20%, 95% CI 14% - 27%; HR 4.40, 95% CI 1.54 - 12.5) which were defined as high risk (score ≥2.1). The risk score's negative predictive value (NPV) for VTE at 30 days was 96% and positive predictive value (PPV) was 20%. The validation cohort (n=97 from 3 external cohorts with routine d-dimer measurement) included 16 (16.5%) patients in the low-risk group and 81 (83.5%) in the high-risk group, with a 30-day VTE incidence of 6.3% (95% CI 0% - 17%) and 21% (95% CI 12% - 30%), respectively (HR 6.22; 95% CI 0.85 - 45.8; p = 0.073)). The NPV (93.7%) and PPV (21%) were comparable to the derivation cohort. The 30-day incidence of major bleeding was 0% (95% CI NR - NR) in low-risk patients (HR 1.36; 95% CI 0.27 - 6.77) and 2.0% (95% CI 0.55% - 5.4%) in the high-risk group. Conclusion: Patients with ALL receiving ASP induction therapy have a 17% VTE risk at 30 days. We derived and externally validated a VTE risk prediction model based upon d-dimer and hemoglobin. This model successfully identifies at least 16.5% of patients with ALL who have a low VTE risk after ASP treatment. Using this model, novel prevention strategies which may be associated with cost and risk could now be tailored to patients with higher risk. Prospective studies are needed to validate the model's performance and role in VTE risk management.

Introduction: Based on a donor versus no-donor analysis, UKALLXII/E2993 showed a survival benefit for adults with acute lymphoblastic leukemia (ALL) who underwent allogeneic hematopoietic cell transplantation (alloHCT) in first complete remission (CR1) compared to consolidation/maintenance chemotherapy alone. The follow-up phase 3 E1910 trial (NCT02003222) randomized BCR::ABL1-negative B-lineage ALL patients (pts) aged 30-70 years in measurable residual disease (MRD)-negative CR1 after intensification to conventional chemotherapy (CC) +/- blinatumomab (blin) and demonstrated significantly improved overall survival (OS) with blin (Litzow, NEJM 2024). The current exploratory subgroup analysis evaluates outcomes of MRD-negative pts randomized on E1910 who underwent alloHCT on trial. Methods: Among pts enrolled on E1910, pts in MRD-negative CR1 by 6-color flow cytometry after intensification who were randomized to CC +/- blin and subsequently underwent alloHCT were identified. We compared baseline characteristics, MRD status post induction, relapse-free survival (RFS) and OS using the Kaplan-Meier method and the two-sided log-rank test and Cox model. A multivariable analysis was performed with alloHCT included as a time-varying covariate as well as a landmark analysis comparing the outcome of pts with unfavorable risk on the CC + blin arm who underwent alloHCT versus those who did not. Results: Of 224 MRD-negative randomized pts, 44 underwent alloHCT on trial: 22 in each arm. The median time from randomization to transplant was 3.2 months (mos). The median follow-up from initial registration was 57.8 mos. Baseline demographics including age (median 55 years), gender (53% male), race (89% white) and ethnicity (89% non-Hispanic/Latino) were equally distributed. Compared to CC + blin, the median peripheral blood white cell (WBC) count and blast percentage at diagnosis were higher in the CC arm at 6,640 vs 3,740/uL and 55 vs 9%, respectively, while median marrow blast percentage and overall unfavorable risk as defined in E1910 (55% vs 64%) were similar. Of the 44 MRD-negative pts who proceeded to alloHCT on study, 77% in the CC arm and 64% in the CC+ blin arm were MRD-negative after induction. Myeloablative conditioning was given to the majority of pts (68% CC arm and 73% CC+blin arm) and the most common graft versus host disease prophylaxis was tacrolimus-based on both arms. Among the 44 pts who underwent alloHCT, the observed hazard ratio (HR) comparing relative risk of death between pts randomized to CC+blin or CC only was 0.59 (95% CI: 0.12-2.11) with a 3-year OS rate of 82% versus 71% and the HR comparing relative risk of relapse/death was 0.52 (CI: 0.15-1.79) with a 3-year RFS rate of 82% versus 67%. For patients with unfavorable risk, 3-year OS and 3-year RFS in each treatment arm were both 71% versus 65%. Among 50 pts with unfavorable risk in MRD-negative CR after intensification who were randomized to CC + blin, a landmark analysis performed at 5 mos post randomization showed 3-year OS and RFS rates of 71% versus 90% and 71% versus 86% between the 14 pts who underwent alloHCT and those who did not, respectively. Receipt of alloHCT was a time-varying covariate in a multivariable analysis with gender, WBC count, platelets, hemoglobin, peripheral blood blasts, bone marrow blasts, performance status, and combined molecular risk category. Age, CD20 status, rituximab use, and intention to receive alloHCT were used as stratification factors. In the entire cohort of MRD-negative pts who were randomized, there was a significant association between improved OS and the receipt of CC+blin vs CC alone (HR 0.46, 95% CI: 0.26 - 0.82; p=0.009), better performance status of 0-1 vs ≥2 and favorable vs unfavorable risk ALL. In contrast, the receipt of alloHCT had no significant effect on OS (HR 1.00, 95% CI: 0.49 - 2.01). Conclusions: Within the constraints of small numbers, this exploratory subgroup analysis demonstrates that in pts with newly diagnosed BCR::ABL1-negative B-ALL treated on E1910 who achieved MRD-negativity after intensification, alloHCT outcomes did not appear to be different with or without blin in consolidation. In a multivariate analysis of all MRD-negative pts, receipt of blin but not alloHCT was associated with improved OS. Further investigation is warranted to characterize the relative benefit of blinatumomab in pts receiving alloHCT in frontline consolidation.

Introduction: Inotuzumab ozogamicin (INO) is an antibody targeting CD22 conjugated with a cytotoxic antitumor antibiotic (calicheamicin) approved for treatment of relapsed/refractory CD22 positive B-cell acute lymphoblastic leukemia (ALL) (Kantarjian et al. NEJM 2017). CD22 is expressed on the surface of lymphoblasts in ALL (~95%). Young adult patients (pts) 18-39 years (yrs) treated on the pediatric regimen CALGB 10403 resulted in a 3-yr event-free survival (EFS) of 59% (95% CI: 52-67%) and an estimated 3-yr overall survival (OS) of 73% (95% CI: 68-78%) (Stock et al. Blood 2019). Alliance A041501(NCT03150693), a phase 3 NCTN sponsored cooperative group trial was conducted to determine if the addition of INO to the CALGB 10403 pediatric regimen would significantly improve EFS. Methods: Eligibility included pts 18-39 years with newly diagnosed CD22 positive ALL, defined as baseline expression in > 20% of lymphoblasts by local institution. Pts with Burkitt-type ALL, BCR::ABL1 positive ALL, or Down syndrome were excluded. Eligible pts received the CALGB 10403 regimen modified to omit extended induction, include dexamethasone as opposed to prednisone as steroid backbone, cap the pegaspargase dose to 3750 units, and adding rituximab for pts with CD20 expression (> 20%). An amendment added blinatumomab for minimal residual disease (MRD) positivity. Pts achieving a complete remission (CR/CRi) or partial remission (PR) were eligible for randomization. Following a 6 pt safety run-in with INO, pts were randomized 1:1 to receive INO or continue CALGB 10403 backbone. Two cycles of INO (1.5 mg/m2/cycle) were administered following induction in the experimental arm. Pts were stratified by age, disease status post induction (M0/M1 vs M2), CD20 status, and LDA Card, which tests for the Ph-like status. The primary endpoint was to determine if the addition of INO would improve the EFS of the pediatric regimen CALGB 10403 without censoring for stem cell transplant (SCT). Key secondary endpoints included the impact of INO on disease-free survival (DFS), OS, and MRD. The Alliance Data and Safety Monitoring Board halted enrollment after 273 out of a planned 341 pts were registered because of increased grade (gr) 5 events in the INO arm compared with the control arm. Results: 273 pts were enrolled between 6/15/2018, and 5/24/2022. Median age was 27.0 yrs, 65.2% were White, 30.4% were Hispanic, and 63.4% were male. Baseline CSF analysis revealed 14% with CNS-2/3 disease. The overall CR rate was 86.8% (82.8-90.8%). 46 pts were not randomized due to death (5), withdrawal (6), ineligibility (3), toxicity (5), receipt of non-protocol therapy (8), progression (5), and other (14). 227 eligible pts were randomized 1:1 to receive INO (N=111) or not (N=116)). For randomized pts, 92.5% achieved M0/M1 marrow status, 48.9% had a positive LDA Card defining Ph-like ALL, 50.7% were CD20 positive. Only 36 pts (13%) received a SCT. With a median follow up of 28.3 months for randomized pts, 3-yr EFS was 69.0% (59.1-80.5%) for the INO arm and 66.7% (57.1-78.1%) for the control (HR=0.97; 0.58-1.63). Similarly, the 3-yr OS was 79.4% (71.0-88.7%) for the INO arm and 80.3% (71.9-89.6%) for the control (HR=1.05; 0.55-2.01). The MRD undetectable rate at Course II Day 56 was 80.6% in the INO arm and 74.2% in the control arm. Univariate analysis suggests improved EFS with INO in pts with a positive LDA card (Ph-like ALL) and of Hispanic ethnicity. There were 22 gr 5 events, 7 occurred prior to randomization. Of the 15 gr 5 events on the randomized cohort, 12 were reported in the INO arm and 3 in the control arm. Of the 12 gr 5 events in the INO arm, all occurred during intensive consolidation courses complicated by prolonged pancytopenia infection/sepsis (8), hepato-biliary in setting of infection (2), multi-organ failure (1), or post-surgical complication (1). These events occurred after INO during Course II (3), Course III (5), or Course IV (4). Conclusions: Although this trial did not meet the primary EFS endpoint for the addition of INO to the pediatric regimen CALGB 10403, these data provide compelling evidence for continued use of pediatric regimens in young adults with ALL as the EFS and OS compares favorably with prior published results. INO may still be efficacious if late toxicity can be mitigated. A pilot study is planned that will decrease INO dose, add 2 cycles of blinatumomab and strict infectious prophylaxis guidelines. Support: U10CA180821, U10CA180882

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for acute lymphoblastic leukemia (ALL) provide recommendations for management of ALL, with a focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. This selection from the NCCN Guidelines for ALL focuses on treatment recommendations for adults with newly diagnosed Ph-negative ALL based on current evidence.

ImportanceKidney light chain (AL) amyloidosis is associated with a risk of progression to kidney replacement therapy (KRT) and death. Several studies have shown that a greater reduction in proteinuria following successful anticlonal therapy is associated with improved outcomes.ObjectiveTo validate graded kidney response criteria and their association with kidney and overall survival (OS).Design, Setting, and ParticipantsThis retrospective, multicenter cohort was conducted at 10 referral centers for amyloidosis from 2010 to 2015 and included patients with kidney AL amyloidosis that was evaluable for kidney response and who achieved at least hematologic partial response within 12 months of diagnosis. The median follow-up was 69 (54-88) months. Data analysis was conducted in 2023.ExposureFour kidney response categories based on the reduction in pretreatment 24-hour urine protein (24-hour UP) levels: complete response (kidCR, 24-hour UP ≤200 mg), very good partial response (kidVGPR, >60% reduction in 24-hour UP), partial response (kidPR, 31%-60% reduction), and no response (kidNR, ≤30% reduction). Kidney response was assessed at landmark points (6, 12, and 24 months) and best kidney response.Main Outcomes and MeasuresCumulative incidence of progression to KRT and OS.ResultsSeven-hundred and thirty-two patients (335 women [45.8%]) were included, with a median (IQR) age of 63 (55-69) years. The median (IQR) baseline 24-hour proteinuria and estimated glomerular filtration rate was 5.3 (2.8-8.5) g per 24 hours and 72 (48-92) mL/min/1.73m2, respectively. In a competing-risk analysis, the 5-year cumulative incidence rates of progression to KRT decreased with deeper kidney responses as early as 6 months from therapy initiation (11%, 12%, 2.1%, and 0% for kidNR, kidPR, kidVGPR, and kidCR, respectively; P = .002) and were maintained at 12 months and 24 months and best kidney response. Patients able to achieve kidCR/kidVGPR by 24 months and at best response had significantly better OS compared with kidPR/kidNR. Kidney progression, defined as a 25% or greater decrease in estimated glomerular filtration rate, was associated with cumulative incidence of progression to KRT and OS.Conclusions and RelevanceThe results of this cohort study suggest that graded kidney response criteria offers clinically and prognostically meaningful information for treating patients with kidney AL amyloidosis. The response criteria potentially inform kidney survival based on the depth of reduction in 24-hour proteinuria levels and demonstrate an OS advantage for those able to achieve kidCR/kidVGPR compared with kidPR/kidNR. Taken together, achievement of at least kidVGPR by 12 months is needed to ultimately improve kidney and patient survival.

The treatment of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) has evolved to include several new options. The NCCN Guidelines for WM/LPL provide a framework on which to base decisions regarding diagnosis, treatment, assessment of response to treatment, and follow-up of both newly diagnosed and previously treated WM/LPL.

The treatment of relapsed/refractory multiple myeloma (MM) has evolved to include several new options. These include new combinations with second generation proteasome inhibitors (PI); second generation immunomodulators, monoclonal antibodies, CAR T cells, bispecific antibodies, selinexor, venetoclax, and many others. Most patients with MM undergo several cycles of remissions and relapse, and therefore need multiple lines of combination therapies. Selecting treatment options for relapsed/refractory MM requires consideration of resistance status to specific classes, and patient-specific factors such as age and other comorbidities should be considered. The NCCN Guidelines for MM provide a framework on which to base decisions regarding workup, treatment, and follow-up of newly diagnosed and previously treated MM. This manuscript outlines the recommendations from NCCN Guidelines for MM specific to relapsed/refractory disease.