Tyrosine Kinase Inhibitors Maintenance Research Articles

Toxicities associated with tyrosine kinase inhibitor maintenance following allogeneic hematopoietic cell transplantation in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Allogeneic hematopoietic cell transplantation (HCT) offers a potential cure in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL); nonetheless, relapses are common and the major cause of mortality. One strategy to prevent relapse is tyrosine kinase inhibitor (TKI) maintenance post-HCT, but published clinical experience is primarily with the first-generation TKI imatinib while data with newer generation TKIs are limited. We conducted a retrospective analysis of 185 Ph+ ALL patients who underwent HCT followed by TKI maintenance from 2003 to 2021 at City of Hope. Initially, 50 (27.0%) received imatinib, 118 (63.8%) received a second-generation TKI (2G-TKI), and 17 (9.2%) received ponatinib. A total of 77 patients (41.6%) required a dose reduction of their initial TKI due to toxicity. Sixty-six patients (35.7%) did not complete maintenance due to toxicity; 69 patients (37.3%) discontinued 1 TKI, and 11 (5.9%) discontinued 2 TKIs due to toxicity. Initial imatinib versus 2G-TKI versus ponatinib maintenance was discontinued in 19 (38.0%) versus 68 (57.6%) versus 3 (17.6%) patients due to toxicity (p = .003), respectively. Patients on ponatinib as their initial TKI had a longer duration of TKI maintenance versus 2G-TKI: 576.0 days (range, 72-921) versus 254.5 days (range, 3-2740; p = .02). The most common reasons for initial TKI discontinuation include gastrointestinal (GI) intolerance (15.1%), cytopenia (8.6%), and fluid retention (3.8%). The 5-year overall survival and progression-free survival for the total population were 78% and 71%, respectively. Our findings demonstrate the challenges of delivering post-HCT TKI maintenance in a large real-world cohort as toxicities leading to TKI interruptions, discontinuation, and dose reduction were common.

Ponatinib Improved the Prognosis of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Japanese Single-Center Cohort Study.

Introduction The overall survival (OS) of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) has improved with the combination of tyrosine kinase inhibitor (TKI) with intensive chemotherapy. In recent years, there has been increased interest in the possibility of long-term survival without allogeneic hematopoietic stem cell transplantation (HSCT) or maintenance therapy. The aim of this study was to determine the effectiveness of treatment and the resultant outcomes in Ph+ALL patients using real-world data. Methods We performed a single-center retrospective analysis utilizing Akita University Hospital data (Akita, Japan) from November 2000 to June 2023 to evaluatethe outcomes of TKI with intensive chemotherapy for Ph+ALL. Results Twenty-three patients with Ph+ALL were treated with intensive chemotherapy combined with TKI, including six imatinib, four dasatinib, and 13 ponatinib. The median patient age was 53 years (range; 28-67). Eighteen patients (78%) achieved complete molecular remission (CMR) within three months. HSCT was performed in 16 patients (70%), all of whom did not receive post-transplant TKI maintenance therapy. Six of the seven patients who did not undergo HSCT received maintenance therapy with ponatinib after intensive chemotherapy. The three-year OSwas 81%. Ponatinib treatment resulted in a much higher OS rate than imatinib/dasatinib (100% vs. 60%;P=0.011). CMR within three months was identified as a prognostic factor for molecular relapse-free survival (hazard ratio (HR)=0.22;P=0.027). CD20 positivity was identified as a risk factor for hematological relapse (HR=5.2, P=0.032). Conclusion Even in a single-center cohort study, ponatinib, as a combination TKI with intensive chemotherapy or maintenance therapy, may improve the prognosis of Ph+ALL. Patients with CMR within three months might not necessarily needto receive HSCT, but a subsequent treatment-free status could have been achieved only by HSCT. Furthermore, CD20 positivity may be a useful biomarker for future treatment decisions in patients with Ph+ALL.

Toxicities Associated with Tyrosine Kinase Inhibitor Maintenance Following Allogeneic Hematopoietic Cell Transplantation in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Background Use of tyrosine kinase inhibitor (TKI) maintenance following allogeneic hematopoietic cell transplantation (HCT) in Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia may help to prevent post HCT relapse but is difficult to administer due to toxicity. However, these toxicities and their impact on maintenance is not fully characterized. Herein, we report our experience at a single, large transplant center to describe toxicities encountered with post HCT TKI maintenance in Ph+ ALL. Methods Ph+ ALL patients (pts) who underwent 1st allogeneic HCT at City of Hope between 2003-2021 and received at least one dose of TKI maintenance were included in this retrospective analysis. Baseline characteristics and toxicities were summarized via descriptive analysis, and groups were compared via Fischer test. Survival analyses were calculated from the time of TKI initiation. Results Baseline characteristics are described in Table 1. Of the 186 pts studied, 50 (26.8%) received imatinib and 136 (73.2%) received a newer generation TKI (NG-TKI: 112 dasatinib, 6 nilotinib, 1 bosutinib, 17 ponatinib) at a median time of 78 days (IQR, 41-134) and 91 days (IQR, 58-129), respectively. A total of 96 patients (51.6%) began TKI maintenance within 90 days of HCT. Post HCT TKI was started prophylactically in 149 patients (80.1%) while 37 patients (19.9%) received TKI preemptively for positive MRD. The MRD status at time of HCT differed between the imatinib group and NG-TKI group. In the imatinib group MRD was negative in 33 of 50 patients (66.0%) compared with 78 of 136 patients (57.4%) in the NG-TKI group (P<0.01). There were 12 (24.0%) vs 18 (13.2%) with an unknown MRD-status at HCT in the imatinib vs NG-TKI groups, respectively ( P<0.01). The median follow-up duration for surviving patients in the entire cohort was 5.5 years (range, 1.0-17.5). The median cumulative TKI exposure was 413.5 days (range, 4-2740). The median cumulative imatinib exposure in patients initially receiving imatinib was 328 days (range, 3-2216), while the median cumulative NG-TKI exposure in patients initially receiving NG-TKI was 268.5 days (range, 3-2740), respectively. The median cumulative exposure of dasatinib, nilotinib, bosutinib and ponatinib were 249 days (range, 3-2740), 222 days (range, 114-839), 371 days, and 576 days (range, 72-921), respectively. Twenty-seven (54.0%) vs 75 (55.2%) patients completed >12 months of initial imatinib and NG-TKI maintenance (P=1.0), respectively. Of the treated patients, 78 pts (41.9%) required at least one dose reduction of their initial TKI due to toxicity; 19 of them (10.2%) required ≥2 dose reductions. When imatinib maintenance was used as the initial TKI, a dose reduction due to toxicity was required in 18 patients (36.0%), of whom 7 patients (14.0%) required ≥2 dose reductions. Initial NG-TKI maintenance required a dose reduction due to toxicity in 60 (44.1%), of whom 12 (8.8%) required ≥2 dose reductions. One hundred and thirty-nine patients (74.7%) had their maintenance TKI therapy interrupted, 122 (65.6%) due to toxicity. Sixty-seven patients (36.0%) did not complete their pre-determined maintenance period owing to toxicity; 70 pts (37.6%) discontinued one TKI, and 11 (5.9%) discontinued two TKIs, due to toxicity. The most common reasons for discontinuing the initial TKI are listed in Table 2, including 45.2% of patients due to toxicity, and 12.9% due to progressive disease. Toxicity-related discontinuations occurred within 6 months on that TKI in 63.0% of patients, and 75.3% within the first 12 months. Five-year overall survival and progression-free survival from the start of TKI were similar between the imatinib and NG-TKI group; 83.1% vs 76.9% (P=0.74) and 72.8% vs 70.5% (P=0.63), respectively (Figure 1). Conclusion Toxicities resulting in dose reductions, interruptions, and discontinuation are common in TKI maintenance post HCT. The toxicity profile (mainly GI and blood count related), frequency, and severity of TKIs in the post HCT setting appears to be different than what has been previously reported in the pre-HCT setting, making it a formidable challenge to meet the recommended cumulative TKI maintenance exposure (2 years) per the NCCN guidelines. While the choice of TKI did not appear to impact on long-term outcomes and relapse rates were not excessive in our analysis, further studies are needed to develop tolerable and personalized TKI maintenance strategies.

Achievement of Undetectable BCR::ABL1 (uBCR::ABL1) Is Predictive of Improved Survival in Philadelphia Chromosome Positive (Ph+ve) Acute Lymphoblastic Leukemia (ALL) Patients Not Receiving Allogeneic Stem Cell Transplantation

Background With the advent of tyrosine kinase inhibitor (TKI)-based therapy the outcome of Philadelphia chromosome-positive (Ph +) acute lymphoblastic leukemia (ALL) has significantly improved. Moreover, patients (pts) who achieved undetectable (u) BCR::ABL1 at 3 months (mo) from the time of initiating therapy, tend to have improved outcomes (Short et al. Blood 2016; 128 [4];504-507). We conducted a retrospective multicenter study to analyze the predictors of achieving uBCR::ABL1 in adult (> 18 years) Ph + ALL pts. Methods A total of 458 adult Ph + ALL pts from 10 US academic institutions, who were diagnosed between May 2003 and April 2023, were evaluated to assess the rates of uBCR::ABL1 at 3 mo after initiating therapy and factors that predict the achievement of molecular response. Continuous variables were summarized as median (range), while categorical variables were reported as frequency (percentage). Unadjusted comparisons of patient/ treatment related characteristics and molecular response were made using a non-parametric test (continuous variables) or Fisher's exact test (categorical variables). Survival curves were estimated using the Kaplan-Meier method and compared between molecular responses via the log-rank test. Results Baseline characteristics The median age of the pts was 53 years (range [R] 19-85), median white blood cell count (WBC) was 17.6 (10 9/L) (R, 1.2-571), 249 (55%) pts had additional cytogenetic (CG) abnormalities, 98 (22%) pts had p210 fusion protein, and 35 (8%) pts had CNS disease at diagnosis. A higher proportion of pts received TKI in combination with intensive chemotherapy (IC) (69%), than TKI + steroids (15%), TKI + low intensity chemotherapy (LC; combination of vincristine, steroids +/- rituximab) (9%), TKI + blinatumomab (3%) and IC without TKI (4%) during induction. During induction, the highest proportion of pts received 2 nd generation TKI combinations (67%; majority dasatinib 98%), compared to imatinib (19%) or ponatinib (10%): 4% of pts did not receive TKI with induction. The complete remission (CR) rate was 94%; measurable residual disease (MRD) negative by flow cytometry 51% (181/352 evaluable pts) and 58.5% (209/354 evaluable pts) of pts had uBCR::ABL1 by PCR at 3 mo from induction. A total of 212 (46%) pts received allogeneic stem cell transplantation (allo-HCT) in CR1, among them 61% of pts received TKI maintenance post allo-HCT. Predictors of uBCR::ABL1 at 3 months Predictors for uBCR::ABL1 at 3 mo are summarized in Table 1. The proportion of pts with WBC > 100 (45% vs 60%, p= 0.04), p210 fusion protein (35% vs 85%, p= <0.001), additional CG abnormality with monosomy 7 (40% vs 61%, p= 0.03), additional somatic myeloid co-mutation (39% vs 61%, p= 0.09; 94 pts evaluable), received induction with steroid plus TKI (41% vs 63%, p= 0.002) or received imatinib based induction (47% vs 61%,p= 0.07) had inferior uBCR::ABL1 rates at 3 mo. Conversely pts who received ponatinib based induction had significantly better uBCR::ABL1 rates (79% vs 57%, p= 0.009). Survival The median relapse free survival (RFS) was 72.3 mo (95% CI; 50.1-94.4), RFS was numerically higher among pts who achieved uBCR::ABL1 at 3 mo but not statistically significant (84.2 mo vs 62.9 mo, p= 0.20). The median overall survival (OS) was 129.2 mo (95% CI; 81.2-177.2), OS was not significantly different among pts who achieved uBCR::ABL1 at 3 mo (129.2) versus no uBCR::ABL1 (not reached; 50% alive at 94 mo), p= 0.47. In sub-set analysis, among non-transplanted pts, RFS was not statistically significant between those who achieved uBCR::ABL1 vs those who did not (38.9 vs 22.0 mo, respectively p= 0.24). However, the median OS was significantly higher in pts who achieved uBCR::ABL1 at 3 mo compared to pts who did not achieve uBCR::ABL1 at 3 mo: 149.3 vs 77.5 mo, p= 0.04 ( Figure 1). Conclusion In this large multicenter study, we observed significantly inferior uBCR::ABL1 rates among pts with WBC > 100, p210 fusion protein, monosomy 7 CG abnormality, pts receiving induction with steroid plus TKI or imatinib based induction. Conversely, uBCR::ABL1 rates were significantly better in pts receiving ponatinib based induction therapy. Overall, we did not see significant impact of uBCR::ABL1 at 3 mo, on RFS or OS. It is likely subsequent therapies and allo-HCT abrogates the negative impact of not achieving uBCR::ABL1 at 3 mo. However, among non-transplanted pts achievement of uBCR::ABL1 at 3 mo showed a significantly improved OS.

Nivolumab Switch Maintenance Therapy After Tyrosine Kinase Inhibitor Induction in Metastatic Renal Cell Carcinoma: A Randomized Clinical Trial by the Interdisciplinary Working Group on Renal Tumors of the German Cancer Society (NIVOSWITCH; AIO-NZK-0116ass)

BackgroundThe role of immune checkpoint inhibitor (ICI) maintenance therapy in metastatic renal cell carcinoma (mRCC) is undefined. ObjectiveTo determine whether switch maintenance therapy with nivolumab improves clinical outcomes in patients with mRCC with tyrosine kinase inhibitor (TKI) sensitivity. Design, setting, and participantsThis open-label phase 2 trial randomized patients with a partial response or stable disease after 10–12-wk TKI induction therapy to either TKI or nivolumab maintenance. Key inclusion criteria were measurable disease, clear cell histology, Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2, and adequate organ function. InterventionIntravenous nivolumab 8 × 240 mg every 2 wk, followed by 480 mg every 4 wk or sunitinib 50 mg (4–2 regimen) or pazopanib 800 mg once daily orally. Outcome measurements and statistical analysesThe primary endpoint was overall survival (OS). Secondary endpoints were the objective response rate (ORR; Response Evaluation Criteria in Solid Tumors v1.1), progression-free survival (PFS), safety (Common Terminology Criteria for Adverse Events v4.03), and patient-reported outcomes (Functional Assessment of Cancer Therapy Kidney Symptom Index). The Kaplan-Meier method, two-sided log-rank tests, and Cox regression models were used for statistical analysis. Results and limitationsMaintenance therapy was nivolumab for 25 patients (51.0%) and TKI for 24 (48.9%). The median age was 65 yr (range 35–79). Nine patients (18.4%) were female, 31 (63.3%) had ECOG PS of 0, and 15 (30.6%) had favorable risk. OS data are immature (17 deaths, 34.7%). The ORR was 20.0% (n = 5) for nivolumab and 52.2% (n = 12) for TKI. PFS was worse with nivolumab (hazard ratio 2.57, 95% confidence interval 1.36–4.89; p = 0.003). Grade ≥3 adverse events occurred in 14 patients (56.0%) with nivolumab and 17 (70.8%) with TKI. A major limitation is early termination of our study. ConclusionsTKI treatment achieved superior ORR and PFS in comparison to nivolumab maintenance therapy. Our data do not indicate a role for nivolumab switch maintenance in mRCC. Patient summaryPatients with metastatic kidney cancer who experienced a tumor response or disease stabilization after a short period of targeted treatment with a tyrosine kinase inhibitor did not benefit from a switch to the immunotherapy drug nivolumab. Patients who continued their original treatment achieved better responses and a longer time without disease progression.This trial is registered on EudraCT as 2016-002170-13 and on ClinicalTrials.gov as NCT02959554.

Outcomes of Tyrosine Kinase Inhibitors Maintenance Therapy with or without Allogeneic Hematopoietic Stem Cell Transplantation in Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia in First Complete Remission: A Systematic Review and Meta-Analysis.

We conducted a systematic review and meta-analysis to compare outcomes of tyrosine kinase inhibitor (TKI) maintenance therapy with or without allogeneic hematopoietic stem cell transplantation (HSCT) in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in first remission (CR1). A literature search was performed on PubMed, Cochrane, and Clinical trials.gov. After screening 1720 articles, 12 studies were included. Proportions and odds ratios (OR) with 95% confidence intervals (CI) were computed. I2 provides an estimate of the percentage of variability in results across studies that is due to real differences and not due to chance. Of 1039 patients, 635 (61%) had TKI alone and 404 (39%) patients had HSCT followed by TKI. At 3 years, a trend towards poor overall survival (OS; OR 0.67, 95% CI 0.39-1.15, I2=68%), (disease-free survival; OR 0.58, 95% CI 0.26-1.29, I2=76%), and higher relapse rate (RR; OR=2.52, 95% CI=1.66-3.83, I2=26%) was seen with TKI alone compared to HSCT-TKI. Although HSCT followed by TKI maintenance in Ph+ ALL has long been considered standard of care, the introduction of potent third-generation TKIs and bispecific T-cell engagers such as Blinatumomab has significantly improved outcomes while sparing the need for HSCT in newly diagnosed patients.

Challenges of Maintenance Tyrosine Kinase Inhibitor Therapy after Allogeneic Hematopoietic Cell Transplantation in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Background: Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) relapse after allogeneic hematopoietic cell transplantation (HCT) is difficult to manage. One strategy to prevent this is tyrosine kinase inhibitor (TKI) maintenance post-HCT, but the vast majority of data discusses the use of imatinib in this setting, with few reports on newer generation TKIs (NG-TKI). Here, we present our institutional experience with TKI maintenance post-HCT. Methods: Ph+ ALL patients who underwent HCT and received TKI maintenance anytime post-HCT from 2003-2019 were included through retrospective chart review. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS), and cumulative incidence of non-relapse mortality (NRM), cumulative incidence of relapse (CIR), and graft-vs-host disease (GVHD). OS and PFS were calculated via the Kaplan Meier method, NRM, CIR, and GVHD were calculated through a competing risk analysis, where CIR was used as a competing risk for NRM and GVHD, and NRM for CIR and GVHD. Results: 110 patients were included, and their baseline characteristics are described in Table 1. 45 (40.9%) patients received imatinib initially, and 65 (59.1%) received NG-TKI initially, of whom, 59 (90.8%) received dasatinib, 4 (6.2%) received nilotinib, and 2 (3.1%) received ponatinib. The median age (range) of the initial imatinib and NG-TKI groups were 42 years (19-64) and 47 (21-73), respectively. 25 (55.6%) vs 43 (66.2%) in the initial imatinib vs NG-TKI groups were >40 years, respectively. 18 (40.0%) vs 39 (60.0%) of the patients receiving initial imatinib vs NG-TKI were female (P=0.052). 20 (44.4%) vs 54 (83.1%) patients in the imatinib vs NG-TKI group underwent HCT ≥2010, respectively (P<0.001). 41 (91.1%) vs 57 (87.7%) in the imatinib vs NG-TKI groups underwent HCT in first complete remission (CR1) (P=0.76), and 21 (46.7%) vs 31 (47.7%) had no measurable residual disease (MRD) detected by PCR at the time of HCT, although 10 (22.2%) vs 10 (15.4%) did not have a PCR report at the time of HCT available (P=0.66). 42 patients (38.2%) required a dose reduction due to toxicity, and 67 patients (60.9%) experienced TKI interruption due to toxicity. Initial imatinib vs NG-TKI maintenance was discontinued in 20 (46.5%) vs 29 (44.6%) due to toxicity, respectively. The median cumulative initial TKI exposure in patients initially receiving imatinib and NG-TKI was 354 days (range, 6-4,473) and 301 days (range, 5-2,740), respectively. Reasons for TKI discontinuation are listed in Table 2. There was no difference in 5-year OS and PFS in patients receiving imatinib vs NG-TKI, 84.1% vs 69.8% (P=0.47) and 75.1% vs 62.5% (P=0.48), respectively. Likewise, 5-year NRM, 5-year relapse, and 4-year GVHD were similar between imatinib vs NG-TKI, 9.0% vs 18.3% (P=0.48), 15.9% vs 19.2% (P=0.92), and 40.7% vs 47.7% (P=0.47), respectively. Univariate analyses showed an improvement in OS and PFS in those who received ≥12 months of TKI maintenance vs those who received <12 months, hazard ratio (HR) 0.26 (95% confidence interval (CI), 0.12-0.55), P<0.001 and HR 0.33 (95% CI, 0.17-0.64), P<0.001. There was no difference in OS and PFS for those who completed ≥12 months of TKI maintenance based on initial TKI of choice, HR 0.85 (95% CI, 0.21-3.51), P=0.8 and HR 0.91 (95% CI, 0.28-2.94), P=0.9. Conclusions: Our findings demonstrate the challenges of delivering post-HCT TKI maintenance. Toxicity leading to TKI interruptions, discontinuation, and dose reduction was common. Post-transplant outcomes were comparable with imatinib and NG-TKI. Therefore, TKI selection for post-HCT maintenance should be based on patient tolerability to maximize TKI maintenance exposure. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Myeloablative Vs Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation in Philadelphia-Chromosome Positive Acute Lymphoblastic Leukemia

Background: Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) has historically been associated with a poor prognosis. Allogeneic hematopoietic cell transplantation (HCT) is recommended in first complete remission (CR1). Strategies to decrease non-relapse mortality (NRM) and to increase the number of patients eligible to receive HCT have led to the utilization of reduced intensity conditioning (RIC) for patients unfit or too old for myeloablative conditioning (MAC), at the cost of a higher risk of relapse. Limited data exist comparing MAC vs. RIC HCT in Ph+ ALL. Here, we compared the outcomes of MAC- and RIC-HCT in Ph+ ALL. Methods: This was a single-center retrospective study examining patients with Ph+ ALL who underwent HCT from 2000-2019. The primary endpoint was progression free survival (PFS), while secondary endpoints include overall survival (OS), graft versus host disease free survival (GRFS), non-relapse mortality (NRM), and cumulative incidence of relapse (CIR), and GVHD. Survival estimates were calculated using the Kaplan-Meier method and differences were examined by the log-rank test. CIR and NRM were calculated using a competing risk analysis and differences were examined by Gray's test. Results: 185 patients were included, of whom, 131 (70.8%) underwent MAC, 128 (97.7%) of whom received total body irradiation (TBI)-based treatment, while 54 (29.2%) underwent RIC, 45 (83.3%) of whom received fludarabine plus melphalan (Flu/Mel). The median age (range) of the patients receiving MAC and RIC were 40 years (19-59) and 57 years (23-73), respectively. 66 (50.3%) vs 7 (13.0%) were ≤40 years in the MAC vs RIC groups (P<0.001). 66 (50.4%) vs 38 (70.4%) in the MAC vs RIC groups underwent HCT ≥2010. 115 (87.8%) vs 47 (87.0%) were in CR1 at the time of HCT in the MAC vs RIC groups (P=1.0), and 41 (31.3%) vs 16 (29.6) had measurable residual disease (MRD) by PCR at the time of HCT, although 34 (26.0%) vs 9 (16.7%) did not have a MRD pre-HCT report available (P=0.31), respectively. 110 (59.5%) received tyrosine kinase inhibitor (TKI) maintenance post-HCT, 73 (55.7%) in the MAC group vs 37 (68.5%) in the RIC group (P=0.14). The rest of their baseline characteristics are described in Table 1. In a sub-analysis of patients in MRD-negative CR1 at HCT, there was no statistically significant difference in 4-year PFS between MAC vs RIC, 71.1% vs 55.7% (P=0.12). PFS was similar in patients receiving TKI maintenance regardless of whether they received MAC vs RIC, hazard ratio 1.73 (95% confidence interval, 0.93-3.22; P=0.08). The 4-year NRM, CIR, and GVHD with MAC vs RIC were 25.6% vs 26.8% (P=0.50), 14.5% vs 21.4% (P=0.27), and 48.4% vs 46.3% (P=0.75), respectively. Conclusions: Patients with Ph+ ALL had similar PFS, OS, and GRFS when treated with MAC vs RIC. RIC-HCT is appropriate in those who would not be expected to tolerate MAC and may also be an acceptable strategy for younger patients when TKI maintenance post-HCT is administered. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Gimema ALL2418: Interim Analysis of a Phase Iia Study of Feasibility and Effectiveness of Inotuzumab Ozogamicin in Adult Patients with B-Cell Acute Lymphoblastic Leukemia with Positive Minimal Residual Disease before Any Hematopoietic Stem Cell Transplantation

Background: Persistence of minimal residual disease (MRD) is associated with a high rate of treatment failure, relapse, and death in B-cell acute lymphoblastic leukemia (B-ALL). Particularly, patients who remain MRD positive before an allogeneic hematopoietic stem cell transplant (HSCT) have an expected disease-related death rate due to the disease of about 60%. The T cell-engager CD19-directed therapy blinatumomab demonstrated considerable efficacy in this setting, however resistant or unsuitable patients have no alternative therapy. Inotuzumab Ozogamicin (IO) is a CD22-directed antibody-drug conjugate with remarkable efficacy in B-ALL with overt disease. Furthermore, IO does not need a high effective immune system to exert activity. Methods: In this multicenter phase 2 trial (NCT03610438), we are investigating the efficacy of IO in obtaining MRD negativity in two cohorts of 38 Ph+ and 38 Ph- B-ALL patients. IO was administered at the dose of 0.5 mg/sqm on days 1, 8, and 15 of a 28-days cycle. Patients who did not obtain MRD negativity after the 1st IO cycle had the option to receive the 2nd IO cycle maintaining the same dosage. Responding Ph- patients received short-term maintenance with low-dose chemotherapy (alternating vincristine, cyclophosphamide, prednisone, methotrexate, and 6-mercaptopurine), responding PH+ patients received tyrosine kinase inhibitor (TKI) for up to 12 weeks, allowing proper IO washout before HSCT. HSCT ineligible patients entered into low-dose chemotherapy or TKI maintenance for up to 2 years. For the primary endpoint, MRD was centrally assessed at baseline, after course 1, after course 2, and eventually before transplant with high sensitive molecular methods for BCR-ABL1 or V(d)J fusion transcripts. Here, we present the results of an unplanned interim analysis that was generated to evaluate the continuation of the study considering the slow accrual due to the Sars-COV2 pandemic. Results: To date, 51 patients underwent screening procedures, and 43 were considered eligible. We report data from the first 39 patients treated in the study. Nineteen out of 39 patients had Ph- B-ALL and 20/39 Ph+ B-ALL. Eighteen out of 39 (46%) patients were male. The median age was 55 years (22-84), 15/39 patients (38%) were older than 65 years. Demographics were comparable between Ph+ and Ph- patients. Within Ph+, ALL 39% of patients harbored p190 and 61% p210 fusion transcript. Within Ph- B-ALL, 1 patient harbored ALL1/AF4 and 1 patient harbored ALL1/ENL fusion transcript. Most of the patients received 1 (16/39, 42%) or 2 (19/39, 50%) previous lines of therapy; 5 patients (13%) were resistant to blinatumomab, and all of them had Ph- B-ALL. Twelve out of 19 (63%) Ph- B-ALL patients received only 1 IO cycle, 7/19 (37%) received 2 cycles; 5/20(25%) Ph+ B-ALL received only 1 IO cycle, and 15/20 (75%) received 2 cycles. To date, central MRD monitoring is available for 20 patients (12 Ph- and 8 Ph+ B-ALL, ongoing for the remaining cases). Overall, MRD negativity was obtained in 7/20 patients (35%); Particularly, in Ph- B-ALL cohort 5/12 (42%) patients achieved MRD negativity, 4/12 (38%) achieved disease reduction at low level MRD positivity (<10-4); in Ph+ B-ALL cohort, 2/8 (25%) patients achieved MRD negativity. One out of 5 (20%) blinatumomab pre-treated patients obtained MRD negative response. IO was an effective bridge to HSCT for 10/39 patients (26%; in patients <65 years old, 9/24 patients, 37%); Specifically, all 7 patients who obtained MRD negativity after IO, a patient with low-positive MRD and 2 patients with non yet available MRD data were bridged to HSCT. Accordingly, with the caveat of a short median follow-up (2.8 months, range 0.6-20.0 months), overall survival in the study population seems promising (figure 1, median OS not reached). Overall, adverse events collected during the study were limited in number and grading. Also, myelotoxicity was manageable. Out of 39 patients, we documented 1 veno-occlusive disease (2.5%) that occurred within 20 days from the last IO dose and before any HSCT. Conclusions: IO administration demonstrated activity with a good safety profile in the setting of MRD positive B-ALL, including blinatumomab resistant patients. Importantly, IO was capable to bridge 37% of eligible patients to HSCT, augmenting the chance to achieve a cure. The continuation of the study will deliver mature efficacy and survival data for a proper evaluation of this promising strategy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

TYROSINE KINASE INHIBITORS MANAGEMENT AFTER ALLOGENEIC STEM CELL TRANSPLANTATION FOR PH+ ALL: LESSONS FROM A PEDIATRIC CHALLENGING CASE

Philadelphia chromosome is found in less than 5% of pediatric but in more than 20% of adults patients with acute lymphoblastic leukemia (ALL). The advent of tyrosine kinase inhibitors (TKIs) lead to a dramatic improvement in the prognosis of these patients, who now have the same stem cell transplantation (SCT) indications as other ALL patients. Recommendations regarding the choice between prophylactic or preemptive strategy, duration of use and the best type of TKI post-SCT need to be better defined. Here we aimed to report a Ph+ ALL pediatric case and to discuss TKI management after SCT. An 9-year-old boy, diagnosed with hyperleukocytic Ph+ B-ALL,mutated IKZF1 and negative CNS was treated according to EsPhALL 2010 protocol. He was poor steroid responder on D8, started imatinib on D14, had 30% of blasts on D15 and 0,4% on D33, persistent positive MRD 0.14% by flow cytometry on week 12. Thus, he was classified as high risk, with allogeneic SCT indication in first remission. He received a 10/10 HLA-matched unrelated SCT from an ABO compatible, male, cytomegalovirus positive donor, with cyclophosphamide, total body irradiation and thymoglobulin for conditioning and cyclosporine plus methotrexatefor graft-versus-host disease prophylaxis. Prophylatic imatinib (100 mg/day) started on D+63 post-SCT. Nevertheless, molecular relapse occurred on D+170. Imatinib was replaced by dasatinib (60 mg/day) and he received three donor lymphocytes infusions (DLI), achieving molecular remission. Due to the occurrence of hematochezia and cytopenias a short suspension and subsequent dose reduction of dasatinib was necessary, after that, he tolerated well 20 mg/day for seven months. After three negative MRD, dasatinib was suspended. Ten months after dasatinib withdrawal, he had an isolated hematological relapse (51% of blasts), at two years post-SCT. He received dexamethasone and dasatinib for cytoreduction followed by IntReALL protocol with hematological remission, but MRD remained positive. Dasatinib was maintained without complications. He received two cycles of blinatumomab, achieving molecular remission. He underwent a second SCT with haploidentical donor in third complete remission. However, he developed severe hepatic venoocclusive disease (VOD) and died on D+48. Several issues related to the TKI usage post-SCT for Ph+ ALL has to be elucidate. The EBMT recommendation of prophylactic imatinib use after SCT,was based on lower relapse rate and better survival reported by a retrospective study in adults patients with imatinib. More recently, a systematic review showed that both prophylactic and preemptive TKIs approaches post-SCT improved survival of patients in CR1 before transplant. Thus, the choice ofpreemptiveuse of TKIs seems to be reasonable, since is less toxic and less immunosuppressive; however, it require a more frequent MRD monitoring by flow cytometry or IgH/TCR PCR and TKIs maintenance until at least one year after MRD negativity. : Our case illustrates the efficacy of dasatinib preemptive associated with DLI in inducing molecular remission. However, it points out that, in addition to the extension of the marrow MRD monitoring period, the duration of TKI use to guarantee the persistence of molecular remission can be long, for more than one year since MRD negativity.

Outcomes of Tyrosine Kinase Inhibitors Maintenance Therapy with or without Allogeneic Hematopoietic Stem Cell Transplantation in Philadelphia Positive Acute Lymphoblastic Leukemia in First Complete Remission: A Systematic Review and Meta-Analysis

IntroductionPhiladelphia positive (Ph+) acute lymphoblastic leukemia (ALL) presents with an aggressive clinical course and carries a high risk for relapse. The addition of tyrosine kinase inhibitors (TKI) has revolutionized the induction and maintenance treatment for this disease and has increased the patients achieving and maintaining complete remission. Allogeneic hematopoietic stem cell transplantation (HSCT) is the standard of care at this time for patients who achieve first complete remission (CR1); however, its impact on outcomes is debated. This systematic review and meta-analysis aimed to compare the outcomes of TKI maintenance therapy with or without HSCT in Ph+ ALL patients in CR1.MethodsFollowing the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted on PubMed, Cochrane, and Clinical trials.gov using MeSH terms and keywords for “ Philadelphia chromosome ”, “hematopoietic stem cell transplantation” and “ protein kinase inhibitors ” from date of inception to May 01, 2021. A total of 1691 records were discovered using database searching. All search results were imported into the Endnote X9.0 reference manager, and duplicates were removed. The primary and secondary screening was performed, and after excluding irrelevant and review articles, a total of 6 (3 retrospectives, 3 phase II randomized controlled trials) original articles were included reporting separate outcomes of TKI maintenance therapy (TKI cohort) and HSCT followed by TKI maintenance therapy (HSCT-TKI cohort) for Ph+ ALL in CR1. Quality evaluation was done using the NIH quality assessment tool. The inter-study variance was calculated using the Der Simonian-Laird Estimator. Proportions along with a 95% Confidence Interval (CI) were extracted to compute pooled analysis using the ‘meta’ package by Schwarzer et al. in the RevMan (version 5.4-1). RESULTSA total of 413 patients from 6 studies were included for this systematic review and meta-analysis. Out of these, 222 (53.8%) had TKI maintenance after consolidation therapy and 191 (46.2%) patients had HSCT followed by TKI maintenance in CR1. The median age of the whole cohort was 49.3 (17-84) years, while the median age for HSCT-TKI patients was 47 (14-84) years. The proportion of males was 26.2% (n=90) in TKI group versus 37.5% (n=137) in the HSCT-TKI group, as reported by 5 studies. The median follow-up was 28 (0.6-149) months. Imatinib mesylate (first-generation TKI) was used in 55.6% (n=125) patients and Dasatinib (second-generation TKI) was given to 44.4% (n=100) patients. (Table 1) Overall survival (OS) was reported from 100% and 93.3% at 1 year to 49% and 33% at 5 years for TKI and HSCT-TKI cohorts, respectively. At median follow-up time of 4 (3-5) years, a trend towards poor OS was seen with TKI group as compared to HSCT-TKI group (OR 0.46, 95% CI 0.17-1.23, I 2=70%); however, the association was not statistically significant. Disease-free survival (DFS) was reported from 49.3% and 71.3% at 4 years to 38.1% and 50.5% at 5 years for TKI and HSCT-TKI cohorts, respectively. At a median follow-up time of 4 (3-5) years, the pooled analysis showed poor DFS for TKI as compared to HSCT-TKI cohort (OR 0.30, 95% CI 0.17-0.53, I 2=0%). Four studies (n=292) reported separate outcomes for relapse, it was 59.1% (87/147) for TKI versus 14.5% (n=21/145) for HSCT-TKI patients, and odds of developing relapse were higher among patients receiving TKI as compared to HSCT-TKI (OR=8.08, 95% CI=3.81-17.14, I 2=0%). ConclusionHematopoietic stem cell transplant in Philadelphia positive acute lymphoblastic leukemia in first complete remission followed by tyrosine kinase inhibitor maintenance therapy confers disease-free and overall survival benefit compared to tyrosine kinase inhibitors maintenance alone. Our findings confirm HSCT as a standard of care in Ph+ ALL in CR1 followed by TKI maintenance and the need for a prospective randomized clinical trial to validate these findings. [Display omitted] DisclosuresLin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Abhyankar: Incyte/Therakos: Consultancy, Research Funding, Speakers Bureau. McGuirk: Astelllas Pharma: Research Funding; Fresenius Biotech: Research Funding; EcoR1 Capital: Consultancy; Novartis: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Pluristem Therapeutics: Research Funding; Bellicum Pharmaceuticals: Research Funding; Novartis: Research Funding; Gamida Cell: Research Funding.

AML-294: Maintenance Therapy After Allogeneic Hematopoietic Transplant for Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis

Context: Allogeneic hematopoietic stem cell transplant (HSCT) is a standard therapy for patients with acute myeloid leukemia (AML), when the risk for relapse overweighs projected transplant-related morbidity and mortality. Disease relapse remains the most common reason for transplant failure and patient death, and treatment of relapse remains extremely challenging. Reducing the risk of post-transplant relapse without unwanted toxicity by means of post-transplant maintenance therapy has recently been studied in several prospective studies. Objectives: We aimed to evaluate the efficacy and safety of maintenance therapy for AML after allogeneic HSCT. Design, Setting and Patients: Systematic review and meta-analysis of randomized controlled trials which compared maintenance therapy with observation or placebo in AML patients after allogeneic HSCT. The Cochrane Library, PubMed, conference proceedings, and references were searched until February 2021. Primary outcome was overall survival (OS). Secondary outcomes included relapse free survival (RFS), relapse rate, and safety (including adverse events and GVHD). Results: Our search yielded five trials conducted between the years 2009 and 2018, including 736 patients, all published in peer-reviewed journals. Maintenance therapy comprised of tyrosine kinase inhibitors (TKI) – i.e., sorafenib - 2 studies and midostaurin - 1 study as well as hypomethylating agents (HMAs), namely decitabine and azacytidine - one study each. Maintenance after allogeneic HSCT was associated with an improved OS, HR=0.61 (95% CI 0.47-0.80). Subgroup analyses by type of maintenance therapy revealed advantage in OS with either TKI or HMA maintenance [HR=0.50 (95% CI 0.33-0.77) and HR=0.69 (95% CI 0.49-0.98), respectively]. Data from five trials was available for RFS analysis and showed improved RFS in the maintenance group compared to the control arm HR=0.51 [95% CI 0.40 - 0.66]. Relapse rate was significantly decreased in the maintenance arm compared to the control arm, RR=0.41 (95% CI 0.20-0.88, 4 trials). Regarding safety, there was no difference between the arms concerning adverse events (AE), including grade 3-4 AE, rate of infections and acute and chronic GVHD. Conclusions: Our meta-analysis shows that post-transplant maintenance therapy in AML patients is effective in decreasing relapse rate and improving RFS and OS, with a satisfactory safety profile.

Maintenance therapy after allogeneic hematopoietic transplant for acute myeloid leukemia: a systematic review and meta-analysis

Background For patients undergoing allogeneic hematopoietic stem cell transplant (HSCT) for acute myeloid leukemia (AML), disease relapse remains the most common reason for transplant failure and patient death. Recent randomized controlled trials (RCTs) have aimed to reduce the risk of relapse by means of post-transplant maintenance therapy. Methods We performed a systematic review and meta-analysis of RCTs comparing the efficacy and safety of maintenance with observation or placebo in patients with AML after allogeneic HSCT. We searched Cochrane Library, PubMed and conference proceedings up to Febuary 2021. Results Our search yielded five trials including 736 patients. Maintenance therapy consisted of tyrosine kinase inhibitors (TKIs) in 3 studies (sorafenib 2 studies; midostaurin 1 study) and hypomethylating agents (HMAs) in 2 studies (decitabine and azacytidine 1 study each). Maintenance therapy was associated with an improved overall survival (OS), HR = 0.61 (95% CI 0.47–0.80). Subgroup analysis revealed advantage in OS with either TKI or HMA maintenance. Relapse free survival (RFS) was also improved in the maintenance arm compared with the control arm HR = 0.51(95% CI 0.40 − 0.66). There was no difference between the two arms in overall grade 3/4 adverse events or overall infections, in grade 3/4 infections, or in acute and chronic graft versus host disease. Conclusions Our meta-analysis shows that post-transplant maintenance therapy in AML patients is effective in improving RFS and OS, with a satisfactory safety profile.

Early Maintenance with Tyrosine Kinase Inhibitors Post Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Improves Survival in Ph+ Acute Lymphoblastic Leukemia (ALL) Patients

Introduction: Addition of tyrosine Kinase inhibitors (TKI) to induction chemotherapy in management of Philadelphia chromosome positive (Ph+) ALL has significantly improved remission rates prior to allogeneic HSCT compared to the pre-TKI era. Consolidation with HSCT further prolongs remission and is potentially curative in the majority of patients. However, relapse is the commonest cause of treatment failure post HSCT with the highest incidence occurring within 18 months post-transplant. One possible strategy to minimize the risk of relapse is to commence TKI maintenance early post transplantation; which is increasingly becoming a common practice in many centers. However long term efficacy of this approach has not been established.Methods: A retrospective search for Ph+ ALL patients undergoing allogeneic HSCT from March 2001 to September 2015 (n=150) at our center was performed. From this cohort to determine the impact of prophylaxis we identified a subgroup of patients (n=99) who were in complete molecular response (CMR) before day +90 post HSCT. Subsequently we performed a day +90 landmark analysis to examine the outcome for patients according to whether or not they had commenced TKI maintenance by day +90 in a univariate and multivariate model. TKI maintenance was recommended but the final decision was based on feasibility and patient/physician preference.Results: Of the 99 patients included in the landmark analysis, 58.6% were men and 41.4% were women. Median age of study participants at the time of HSCT was 40 (range 3-64) years with a median follow up duration of 5.2 (range 1.1-15.0 ) years. At time of HSCT, 74.7% patients were in CR1, 16.2% were in CR2, and 9.1% were beyond CR2 or had primary induction failure. The majority of patients (97%) received a myeloablative preparative regimen, including radiation therapy in 31.3%. The median duration of TKI maintenance was 12.1 months (range 1-74 months). Imatinib was the commonest TKI used. Patients who received TKI maintenance (n=38) had superior 10-year probability of PFS and OS compared to patients who did not receive maintenance (n=61) at 68.1% vs 44.8%, p=0.005, and 67.1% vs 47.8%, p=0.004, respectively (Figure 1). TKI maintenance (HR=0.282, CI=0.122-0.654, p=0.001) and disease status pre-HSCT (beyond CR1) (HR=2.909, CI=1.286-6.577, p=0.01) were the two independent predictors for PFS in the multivariate model. Similarly, TKI maintenance (HR=0.244, CI=0.098-0.608, p=0.001) and disease status pre-HSCT (beyond CR1) (HR=3.394, CI=1.449-7.948, p=0.03) were the two independent predictor for OS. Both groups appeared to be well matched for several transplant/disease/treatment related variables.Conclusion: Prophylactic TKI maintenance early post allo-SCT is feasible and is associated with improved PFS and OS. Future prospective studies are needed to define the optimal duration of TKI maintenance to further improve outcomes for this historically adverse group. [Display omitted] DisclosuresOran:Celgene: Research Funding; AROG: Research Funding; Astex: Research Funding. Jabbour:Bristol-Myers Squibb: Consultancy. Kantarjian:Bristol-Meyers Squibb: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Amgen: Research Funding; ARIAD: Research Funding; Delta-Fly Pharma: Research Funding.

FLT3 ITD AML Outcomes Are Impacted By Exposure to One Cycle of Cytarabine Based Consolidation, Pre- and Post-Transplant TKI Therapy, and Presence of Minimal Residual Disease (MRD) Prior to Allogeneic Blood or Marrow Transplant

Background:FLT3 ITD AML is associated with high rates of relapse and short relapse free survival. Prognosis after relapse is extremely poor, making optimization of initial therapy for this group of patients important. Most data now suggest allogeneic transplant should be the standard consolidation for FLT3 ITD AML. Although peri-transplant tyrosine kinase inhibitor (TKI) use is common, there is no consensus on the best way to incorporate TKIs into the management of these patients. A comprehensive review of treatment outcomes is needed to determine which strategies reduce the risk of relapse and prolong survival.Methods:We conducted a retrospective chart review for 112 patients with FLT3 ITD mutations seen at JHH between 2005 and 2016 who underwent bone marrow transplantation to collect demographic, diagnostic, transplant and survival data. Differences in the distribution of demographic, clinical, and biological characteristics were analyzed for significance using Fisher's exact test. Consolidation was defined as any cytarabine-based regimen after remission induction therapy. MRD positivity included the presence of >0 to 5% abnormal blasts by morphology or flow cytometry and/or persistence of genetic abnormalities (cytogenetics, mutation panels) prior to transplant. Overall survival (OS) was defined as the time interval from date of transplant to date of death from any cause or to last follow up visit. Relapse free survival (RFS) was defined as the time interval from date of transplant to date of relapse or death from any cause. Survival was censored at 2 years post-transplant. Time was censored at the last follow-up visit if relapse or death were not observed. Survival estimates were calculated using Kaplan-Meier method and comparison of survival distributions were done using log-rank test. TKI included are quizartinib, sorafenib, and gilteritinib.Results:Patient characteristics are summarized in Table 1.Outcomes based on disease characteristics including NPM1 status, allelic ratio and cytogenetics are listed in Table 2. Patients with NPM1 mutations had improved RFS (HR=0.4165, p=0.0193). Patients with no detectable MRD prior to transplant have improved RFS (HR=0.4394, p=0.0023) and OS (HR=0.5526, p=0.0437).Outcomes related to treatment strategies are also summarized in Table 2. Patients with at least 1 cycle of post remission consolidation had lower rates of MRD (p=0.0046) (Table 3), and improved RFS (HR=0.5191, p=0.0228) and OS (HR=0.4728, p=0.0143) (Figure 2). Patients who received consolidation and pre-transplant TKI had the best outcomes (Figure 1). In the absence of consolidation, pre-transplant TKI usage was associated with longer RFS (median 1.819 years versus 0.8548 years, p = 0.2105) and OS (median 1.995 years versus 1.249 years, p=0.4384) compared to those with no pre-transplant TKI use. Patients who received either consolidation or pre-transplant TKI had similar outcomes. Non-myeloablative conditioning regimens trended toward favorable outcomes over myeloablative regimens despite older patients and lower rates of NPM1 mutations (HR=.6358, p=0.1346 for OS, HR=0.6471, p=0.1231 for RFS). There was no difference in OS or RFS between matched and haploidentical donors. Post-transplant TKI use improves RFS (HR=0.5503, p=0.0339) and OS for all patients (HR=0.4679, p=0.0102). For patients who had MRD prior to transplant, TKI use post-transplant was associated with median RFS of 1.499 years versus 0.7425 years for those who did not use post-transplant TKI (Figure 2). Post-transplant TKI use also improved OS (HR=0.3737, p =0.0308) for patients without MRD prior to transplant.Discussion:Remission status at time of transplant is key to outcomes. Consolidation, as well as use of TKI pre- and post-transplant are associated with favorable outcomes. Although patients who were given consolidation had more favorable outcomes, it is unclear if patient characteristics (higher NPM1 %, lower AR>50%, and younger age) confounded their outcomes. Matched and haploidentical donors confer similar outcomes. This data supports treatment of FLT3 ITD AML patients to include induction, 1 cycle of post remission consolidation, TKI use prior to transplant, and transplant with post-transplant TKI maintenance. [Display omitted] DisclosuresSmith:Celgene: Consultancy; Curis: Consultancy; Ariad/Takeda: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Swinnen:Genentech: Consultancy; Pharmacyclics: Consultancy. Levis:Astellas Pharma Us: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; FujiFilm: Research Funding; Daiichi Sankyo, Inc.: Consultancy, Honoraria.

Pharmacodynamic Monitoring of Targeted Therapy with Midostaurin By Plasma Inhibitor Activity (PIA) Analysis in FLT3 -ITD Positive AML Patients Enrolled in the AMLSG16-10 Trial: A Study of the AML Study Group (AMLSG)

Background: The multi-targeted tyrosine kinase inhibitor (TKI) Midostaurin has recently been approved by the FDA for the treatment of newly diagnosed acute myeloid leukemia (AML) with FLT3 -ITD mutation in combination with intensive standard chemotherapy (Stone et al. NEJM 2017). Monitoring of the efficacy of such a targeted therapy and correlation of the results with clinical outcome is of major importance. The plasma inhibitor activity (PIA) assay allows to determine the level of dephosphorylation of the target under TKI therapy, which is suggested to correlate, as a marker for activity, with clinical outcome.Aim: To individually measure the level of FLT3 dephosphorylation by PIA analysis in a large cohort of FLT3 -ITD positive AML patients (pts) treated in our AMLSG16-10 trial (NCT: NCT01477606) and to correlate the results with clinical outcome.Methods: Plasma samples from 118 pts (age 18-70 years) with newly diagnosed FLT3 -ITD positive AML were obtained at defined time points during and after therapy for PIA analysis. Pts were enrolled in the ongoing AMLSG16-10 trial (NCT01477606) applying intensive therapy in combination with Midostaurin (continuous dosing except days of chemotherapy). For consolidation therapy, pts proceeded to allogeneic hematopoietic stem cell transplantation (alloHSCT) as first priority; pts not eligible for alloHSCT were intended to receive 3 cycles of age-adapted high-dose cytarabine (HiDAC) with Midostaurin from day 6 onwards, followed by 12 28-day cycles of Midostaurin maintenance therapy. PIA analyses were performed at day 15 and at the end of each induction and consolidation cycle, monthly during maintenance therapy and every three months during follow-up.Results: So far, 946 plasma samples from 118 pts have been analyzed during (n=116) and after (n=136) 1st and 2nd induction cycle, during (n=104) and after (n=122) consolidation therapy as well as during maintenance therapy (n=346) and the follow-up period (n=122). The strongest reduction of FLT3 phosphorylation (p-FLT3) was observed at the end of 1st induction to 41.3% p-FLT3 (median; range, 0.3-100%). During treatment p-FLT3 levels increased again up to 80.2% (median; range, 32.6-100%), while during maintenance therapy p-FLT3 levels subsequently decreased down to 48.5% (median; range, 15.7-100%). P-FLT3 levels stratified by the median (41.3%) obtained after the 1st induction cycle were not associated with clinical or genetic features and they had no impact on response to induction therapy. So far, pts with a p-FLT3 level below that median showed an in trend better overall survival (OS) (P= .09), while there was no effect on event-free survival (EFS) and the cumulative incidence of relapse (CIR) between pts with p-FLT3 below or above the median level (P= .11 and P= .80, respectively). In addition, we also evaluated if a lower value (20%) for p-FLT3 levels allows to better discriminate pts with regard to their clinical outcome. However, there was no difference for the clinical endpoints OS, EFS and CIR between pts with target inhibition of >80% and <80% (P= .21, P= .75 and P= .58, respectively).Conclusions: In our study of FLT3 -ITD positive AML pts treated with Midostaurin in combination with intensive chemotherapy the strongest target inhibition was reached after the 1st induction cycle indicating the highest TKI activity against FLT3 at that time point. First correlations with clinical outcome suggest that p-FLT3 levels below the median after the 1st induction cycle may correlate with better overall survival. Interestingly, target-inhibition was not maintained during subsequent treatment cycles in most of the pts, while a more sufficient inhibition of p-FLT3 was again achieved during TKI maintenance therapy. It has to be determined if loss of stable target-inhibition during treatment might be triggered by the combination of the TKI and concomitant standard chemotherapy. In addition, effects of Midostaurin maintenance therapy have to be evaluated in larger patient cohorts. DisclosuresSchroeder:Celgene: Consultancy, Honoraria, Other: travel support. Salwender:Amgen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Honoraria and travel support: Janssen Cilag, Celgene, BMS.: Honoraria, Other: Travel support; Takeda: Honoraria. Fiedler:Amgen, Pfizer: Research Funding; Amgen: Patents & Royalties; Amgen, Gilead, GSO, Teva, Jazz Pharmaceuticals: Other: Support for meeting attendance; Amgen, ARIAD/Incyte: Membership on an entity's Board of Directors or advisory committees. Götze:Celgene: Honoraria; Novartis: Honoraria; BMS: Honoraria; Abbvie: Honoraria. Kindler:Novartis: Membership on an entity's Board of Directors or advisory committees. Döhner:Novartis: Honoraria, Research Funding.

TKI Maintenance After Stem-Cell Transplantation for FLT3-ITD Positive Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis

This analysis aimed to systematically review and synthesize the existing evidence regarding the outcome of tyrosine kinase inhibitor (TKI) maintenance therapy after allogeneic stem-cell transplantation for patients with FLT3-ITD-mutated acute myeloid leukemia (AML). We searched publicly available databases, references lists of relevant reviews, registered trials, and relevant conference proceedings. A total of 7 studies comprising 680 patients were included. Five studies evaluated sorafenib and 2 studies evaluated midostaurin, compared with control. The incidence of relapse was significantly reduced after TKI therapy, showing an overall pooled risk ratio (RR) of 0.35 (95% confidence interval [CI], 0.23-0.51; P < 0.001), with a marked 65% reduced risk for relapse. The overall pooled RR for relapse-free survival and overall survival showed significantly improved outcome after TKI maintenance therapy, being 0.48 (95% CI, 0.37–0.61; P < 0.001) and 0.48 (95% CI, 0.36–0.64; P < 0.001). The risk for relapse or death from any cause was reduced by 52% using TKI. No difference in outcome was seen for non-relapse mortality, and the risk for chronic or acute graft-vs. -host disease appeared to be increased, at least for sorafenib. In conclusion, post-transplant maintenance therapy with TKI was associated with significantly improved outcome in relapse and survival in patients with FLT3-ITD positive AML.

Skuteczne odstawienie nilotynibu po niepowodzeniu terapii imatynibem

Zastosowanie inhibitorów kinaz tyrozynowych (TKI) w leczeniu przewlekłej białaczki szpikowej (CML) spowodowało zrównanie długości życia chorych z czasem przeżycia oczekiwanym w zdrowej populacji. Obecnie, coraz częściej, celami terapeutycznymi, do których dążą zarówno lekarz hematolog, jak i jego pacjent jest odstawienie TKI i utrzymanie tak zwanej remisji wolnej od leczenia (TFR). Jest to możliwe w 40–50% przypadków u chorych na CML, którzy osiągnęli stabilną głęboką odpowiedź molekularną (DMR). Poniżej przedstawiono opis przypadku pacjentki z CML, u której z powodu niepowodzenia terapii imatynibem wdrożono leczenie nilotynibem. Po kilku latach utrzymującej się stabilnej DMR nilotynib odstawiono. Ponad rok od tej decyzji pacjentka pozostaje w TFR.

Discontinuation of Maintenance Tyrosine Kinase Inhibitors in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia outside of Transplant

Background: The addition of tyrosine kinase inhibitors (TKIs) to chemotherapy has dramatically improved outcomes of patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). When allogeneic hematopoietic stem cell transplant (HSCT) is performed, maintenance TKI is generally given for a fixed duration. However, the optimal duration of TKI outside of HSCT remains unknown, and the common practice is to continue indefinitely. Here, we report characteristics and outcomes of 9 patients treated with chemotherapy + TKI without HSCT and later discontinued TKI. Methods: Among 188 patients with Ph-positive ALL who did not undergo HSCT, 9 of them discontinued maintenance TKI mainly due to side effects. Patients were closely monitored with serial PCR testing for the BCR-ABL1 transcript. Major molecular response (MMR) was defined as BCR-ABL1 transcript ≤0.1% on the international scale for p210 transcripts and a 3-log reduction from baseline for p190 transcripts. Deep molecular remission (DMR) was defined as the absence of quantifiable BCR-ABL1 transcripts with a sensitivity of 0.01%. Molecular relapse was defined as loss of MMR. Treatment-free remission (TFR) was defined from time of TKI discontinuation to molecular relapse, last follow-up, or death from any cause. Results: At the time of TKI discontinuation, transcript level was undetected in 6 patients, <0.01% in 2 patients, and 0.01% in another patient. Prior to discontinuation, the median duration of TKI therapy and of DMR was 70 and 47 months, respectively. No morphological relapse occurred. Three patients (33%) had molecular relapse at a median of 6 months. All 3 resumed TKI therapy, and 2 of them regained DMR after a median of 13 months. After a median follow-up of 49 months, the median TFR was not reached, and the 4-year TFR rate was 65%. The median duration of DMR in patients with and without molecular relapse was 22 and 58 months, respectively (p = 0.096). Conclusion: TKI discontinuation outside of HSCT in Ph-positive ALL in the setting of compelling toxicity may be safe only among a highly selected group of patients with deep and prolonged DMR undergoing close and frequent monitoring. Validation of these findings in prospective clinical trials is highly needed.

Health Insurance Status Impacts Rates of Overall Survival in Philadelphia-Positive Acute Lymphoblastic Leukemia

Introduction: The Philadelphia chromosome is associated with a poor prognosis in patients with acute lymphoblastic leukemia (ALL). Prior to the use of hematopoietic stem cell transplantation (HSCT) and tyrosine kinase inhibitors (TKIs), Philadelphia-positive (Ph+) ALL patients were found to have an overall survival (OS) rate of less than 20% over the course of 3 years (Thomas et al., Blood 2004). While modern day therapies including allogeneic HSCT and newer-generation TKIs such as dasatinib have led to significant improvements in OS for this population, these treatments have variable accessibility due to costs for patients with limited to no health insurance. Methods: We performed a retrospective study at the Norris Comprehensive Cancer Center and Los Angeles County Hospital, both associated with the University of Southern California, to investigate outcomes in Ph+ ALL adults with different types of health insurance. Individuals included in the study were diagnosed with Ph+ ALL between 2004-2019. Health insurance options included private insurance, Medicare, Medicaid, or no insurance. Treatment modalities included allogeneic HSCT followed by maintenance TKI therapy or combination chemotherapy plus a TKI. The former was preferred if patients met the key transplant eligibility criteria of insurance coverage and caregiver availability at home. Patient OS was defined as the time from diagnosis of Ph+ ALL until patient death. Statistical analysis was performed using the Fisher's exact probability test with two-tailed p-values &lt;0.05 deemed significant. Results: A total of 81 patients with Ph+ ALL were included in this study. Forty-seven patients (58%) were male and the median age at the time of diagnosis was 45 years (range 20-70). Two groups of patients were compared: those with either Medicare or private insurance (M/P) versus those with Medicaid or no insurance (M/N). Thirty-three patients (40.7%) were included in the M/P group and 48 patients (59.2%) in the M/N group. In comparing rates of OS, the 1-year OS was 100% vs. 85.1% (p = 0.038), 2-year OS was 96.2% vs. 75.8% (p = 0.033), and 3-year OS was 88.2% vs. 59.2% (p = 0.049) for M/P patients compared to M/N patients, respectively (Figure 1). In terms of treatment, there was a significant difference in the number of patients eligible to undergo allogeneic HSCT as 20 patients (60.6%) in the M/P group were able to be transplanted in contrast to 15 patients (31.3%) in the M/N group (p = 0.012). There were similar rates of caregiver availability to support HSCT between both groups; 24 M/P patients (72.7%) lived with a caregiver versus 33 M/N patients (68.8%) in comparison (p = 0.806). Furthermore, there were significantly more patients in the M/P group who were able to be treated with the newer-generation TKI dasatinib instead of the older agent imatinib compared to M/N patients (100% vs. 85.4%, p = 0.038). Conclusion: With the emergence of allogeneic HSCT and newer-generation TKIs, the rates of OS in the Ph+ ALL population improved dramatically from the prior era (Fielding et al., Blood 2009). However, barriers still exist to receiving these modern therapies, one of the most formidable being sufficient insurance coverage of costs. This study demonstrated that the Ph+ ALL population in the M/P group had significantly higher rates of OS at the 1-year, 2-year, and 3-year marks compared to those in the M/N group. Furthermore, there were also a greater percentage of patients in the former group who were able to undergo allogeneic HSCT during the study period. While eligibility for allogeneic HSCT depended on caregiver availability in addition to insurance status, there were similar rates of caregivers between the two groups, thus implying that this factor had no major impact on the differing rates of HSCT. Dasatinib was previously shown to have increased potency in inhibiting the in vitro growth of cells with wild-type BCR-ABL compared to imatinib, making it a preferred choice for TKI therapy (Li, Leukemia &amp; Lymphoma 2008). There were again significantly more M/P patients than M/N patients who were able to be treated with dasatinib rather than imatinib. Given that health insurance status was found to be correlated with rates of OS, allogeneic HSCT, and the availability of newer-generation TKIs, it remains a critical point of discussion in the treatment of Ph+ ALL patients from all socioeconomic backgrounds. Disclosures No relevant conflicts of interest to declare.