High-risk Adult Acute Lymphoblastic Leukemia Research Articles

Superior survival with allogeneic hematopoietic stem cell transplantation versus chemotherapy for high-risk adult acute lymphoblastic leukemia in a PDT-ALL-2016 pediatric-inspired cohort.

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Long Term Durable Responses in Relapsed/Refractory (r/r) ALL, DLBCL, and FL Patients Treated with Tisagenlecleucel and Its Association with Persistence of CAR T-Cells

Introduction: Monitoring of chimeric antigen receptor (CAR) transgene levels in peripheral blood post tisagenlecleucel (tisa-cel) infusion provides information on expansion and persistence of CAR T-cells. In adult diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) patients (pts), the expansion of CAR T-cells was similar between responding and non-responding pts, while in pediatric and young adult acute lymphoblastic leukemia (ALL) pts, higher expansion in responding pts was observed. Based on long term follow up data from tisa-cel treated pts, analyses were performed to delineate the impact of CAR persistence and B cell aplasia on duration of remission (DOR). Methods: Transgene levels in blood measured by quantitative polymerase chain reaction were available from pivotal phase II studies in pts with r/r ALL (ELIANA [N=79], ENSIGN [N=64], NCT03123939 [N=69], NCT01626495 [N=60]), r/r DLBCL (JULIET [N=115]), and r/r FL (ELARA [N=97]), along with the long term follow up study (NCT02445222). The time related to loss of persistence of CAR T-cells (T loss) was defined as the time at which transgene levels first dropped below 50 transgene copies/µg DNA (approximates to lower limit of quantification (LLOQ) of the assay) after maximal expansion. Kaplan Meier analysis was performed to investigate the impact of duration of T loss and time corresponding to last quantifiable level (T last) on DOR/relapse. The impact of time to B cell recovery (>1% CD19+ B cells/WBCs or >3% CD19+ B cells/lymphocytes for ALL, and 80-616 cells/µL for DLBCL and FL), on DOR/relapse was also investigated. Results: Long term CAR persistence in tisa-cel treated pts has been observed for up to 9, 6, and 2.5 years for ALL, DLBCL, and FL pts, respectively, reflecting differing length of follow up based on initiation of trials in respective indications. Across indications, pts who lost transgene within 6 months or between 6-12 months had shorter DOR relative to pts with persistent transgene (Fig 1, ALL pts). In ALL, the median T loss was 27.4, 18.2, 9.7, and 18.0 months for ongoing complete response (CR) > 12 months, CR pts between 6-12 months, relapsed pts < 12 months, and relapsed pts > 12 months, respectively. However, of the pts who lost transgene within first 6 months, some pts maintained durable responses for ≥12 months (29%, 15%, and 50% in ALL, DLBCL, and FL, respectively). Among ALL relapsed pts, majority (17/26, 65%) of the pts with T loss < 6 months showed B cell recovery, however 6 pts had T loss at < 6 months as well as B-cell recovery but maintained response for ≥ 12 months. In ALL, Pulsipher et al.,(Blood Cancer Discov. 2022)have shown that NGS MRD within the first 6 months to 1 year post infusion may be a more reliable predictor of potential relapse than B cell recovery. The median time to B-cell recovery was 266 days in pts who relapsed/censored within 12 months but was not reached for pts with ongoing response at 12 months. On the contrary, B cell recovery seems to have no association with relapse in DLBCL or FL pts. Of the ALL pts with CAR persistence, pts with <50% morphologic blasts at any time prior to infusion of tisa-cel had longer DOR compared to pts with ≥50% blasts. This may also reflect a more resistant high risk ALL at the time of study entry or greater potential for stochastic loss of CD19 in pts with the higher disease burden. Conclusions: Long term sustained remission/response was observed in tisa-cel treated pts in the pivotal trials. The analyses demonstrate a positive association between CAR persistence and durable clinical responses across indications, however, some pts maintained durable responses despite early loss of transgene and/or early B cell recovery (< 6 months post infusion; Myers et al., J Clin Oncol. 2021). To note, in DLBCL and FL, the transgene levels in blood may not represent the levels at target sites including lymph nodes, moreover, T last and T loss are dependent on the duration of follow up, LLOQ etc. Of note, these analyses represent data from pivotal tisa-cel clinical studies with a heavily treated pt population post multiple lines of therapy including prior HSCT, and may not represent pts treated with commercial product, at earlier times post diagnosis in current studies with fewer lines of prior treatment, lower pre-infusion disease burden, and/or other CAR product. In pts with early loss of transgene, further research is needed to identify potential factors or patient characteristics resulting in durable responses.

Higher Survival Advantage with Hyper-CVAD Chemotherapy Regimen Before Allogeneic Stem Cell Transplantation in Patients with High Risk Adult Acute Lymphoblastic Leukemia: Two-Center Experience

While promising results have been achieved in the treatment of childhood, the optimal initial treatment for adult acute lymphoblastic leukemia (ALL) has not yet been defined. Hyper-CVAD has become a widely used treatment for approximately 2 decades in the treatment of adult ALL. We conducted a retrospective analysis of 30 patients treated with Hyper-CVAD at two centers between 2014 and 2020. In all (n=30) patients treated with Hyper-CVAD, complete response (CR) rate was 86.7%, induction mortality was 10%, refractory disease was 3.3%, the median overall survival (OS) was 38 months (95% CI 7.78–68.2 months), the median disease-free survival (DFS) was 29 months (95% CI 9–49 months), the 2-year OS rate was 56.5%, and the 2-year DFS was rate 56.7%. For standard risk (n=12) ALL patients, the median OS was 20 months (95% CI 0–43 months), and median DFS was 7 months (95% CI 0–25 months). For high risk (n=18) ALL patients, the median OS was 38 months (95% CI 0–76 months), and median DFS was not reached. These results indicate that Hyper-CVAD regimen should be considered as an option for induction treatment of adult ALL patients who are newly diagnosed and eligible for allo-HSCT.

Dual Targeting of MDM2 and BCL2/Bclxl Demonstrates Potent Synergistic Activity in High-Risk Adult Acute Lymphoblastic Leukemia

Despite the use of both intensive multi-modal cytotoxic therapeutic regimens and novel immune-based therapies in adult acute lymphoblastic leukemia (ALL) outcomes remain dismal, with five-year survival rates less than 45%. As such, there is an urgent need to identify novel therapies to improve patient outcomes. While TP53 mutations are infrequent in ALL, alternative mechanisms such as MDM2 overexpression or CDKN2A/B deletion may otherwise phenotypically disrupt and circumvent normal p53 function. We previously demonstrated encouraging pre-clinical activity of p53-MDM2 antagonist idasanutlin (RG7388) in diverse high-risk primary and patient-derived xenograft (PDX) ALL samples at concentrations well-below clinically attainable plasma levels [Bell et al., ASH 2020]. However, clinical studies reveal only modest responses to idasanutlin monotherapy in various hematological malignancies, emphasizing the need to identify effective drug combinations. To systematically identify combination treatments which enhance cytotoxic idasanutlin activity, we performed comprehensive high-throughput phenotypic combination screening against 1971 FDA-approved and clinically advanced drugs. Extensive use of an ex vivo coculture system of ALL blasts and hTERT-immortalized mesenchymal stem cells (MSCs) was employed to support growth and survival of the ALL blasts, complemented by high-content image analysis to discriminate and enumerate the respective cell populations. Using the relapsed NALM6 B-ALL cell line and a panel of 6 PDX ALL samples - including relapsed and high-risk cytogenetic subtypes - we iteratively identified drugs (n=10) exhibiting significant synergistic and potent interaction with idasanutlin at concentrations well-below respective drug peak plasma concentrations reported in patients (Bliss synergy δ > 10). These included clinical ALL drugs dexamethasone and daunorubicin, proteasome inhibitor carfilzomib, BCL2/BCLxL inhibitor navitoclax, and histone deacetylase inhibitors romidepsin and pracinostat. Counter-screening of each drug candidate in a NALM6 TP53-isogenic cell model confirmed on-target p53-dependent combination activity (p<0.05). Further interrogation of each drug candidate was performed across a broad landscape of drug combination ratios with idasanutlin in primary (n=5) and PDX samples (n=6), including high-risk KMT2A-rearranged, ABL class T-ALL, and ETP-ALL. Combination of idasanutlin with navitoclax exhibited both the greatest and most consistent synergistic interaction (δ = 24.7±8.7, n=11) of the candidate combinations (n=10) across an extensive landscape of dose combinations; additionally alluding to synergy indiscriminate of ALL subtype. Further characterizing the cytotoxic antileukemic activity of navitoclax, single-agent exposure achieved low nanomolar range, dose-dependent ex vivo sensitivity in a panel of B- (n=10) and T-ALL (n=4) primary and PDX samples, with half maximal inhibitory concentrations (IC50) in the range of 3 to 11 nM (mean IC50 = 6.4 nM) - almost 1000-fold lower than clinically attainable concentrations [Roberts et al., BJH2015]. While both idasanutlin and navitoclax effectively induced apoptosis in their own right, combination exposure markedly enhanced cell death. In an exceptionally high-risk TCF3-HLF PDX sample, 24 hours exposure to the drug combination increased annexin-V positive cells by 37.3±5.0% and 33.3±3.5% as compared to either drug (IC50s, p<0.0001). In the NALM6 and RS4;11 relapsed ALL cell lines, combination exposure significantly increased annexin-V positive cells by at least two-fold (p<0.001) and enhanced apoptotic hallmark products cleaved poly(ADP-ribose) polymerase (PARP) (p<0.01) and cleaved caspase-3 as compared to either drug alone (IC50s). Mechanistically, we found protein levels of MCL-1-binding pro-apoptotic sensitizer NOXA to be up to 3-fold increased in combination-treated blasts (p<0.05), potentially inhibiting compensatory anti-apoptotic MCL-1 activity - a known clinical resistance factor to BH3 mimetics. Together, we provide strong evidence that concurrent targeting of MDM2-p53 binding and BCL2/BCLxL leads to potent and synergistic enhancement of apoptotic cell death in a range of high-risk ALL subtypes. The proposed combination of two clinical-stage compounds could have considerable positive clinical impact for the treatment of adult ALL.

Non-TBI Based Conditioning Regimen in Peripheral Blood Stem Cell Transplantation (PBSCT) for Adult Acute Lymphoblastic Leukemia Patients: A Single Center Experience

Introduction: The outcome of adult acute lymphoblastic leukemia (ALL) patients with chemotherapy only is not promising and overall survival (OS) does not exceed 30%. Allogeneic Hematopoietic Stem Cell transplantation (allo-HSCT) in first or beyond complete remission (≥CR1) has shown a superior OS rate of approximately 50 % over conventional chemotherapy protocols. Total body irradiation plus Cyclophosphamide (TBI/Cy) and oral busulfan plus cyclophosphamide (BU/Cy) are commonly used myeloablative conditioning regimens in ALL. TBI-based conditioning regimen is considered the standard of care.Aim: To compare the outcomes of allo HSCT using TBI/Cy and BU/Cy conditioning regimens in adult standard and high risk ALL patients in ≥CR1.Material and methods: We retrospectively analyzed the outcome of TBI/Cy and BU/Cy myeloablative conditioning regimen (MAC). BU/Cy cohort included 33 patients (9 females & 24 males) with a median age of 28 years (19-42). Myeloablative BU oral dose was 16mg/kg/4 days & Cy dose was 120 mg/kg IV over 4 days. TBI/Cy cohort included 45 patients (14 females & 31 males) with a median age of 24 years (19-46). TBI dose was 12 Gy fractionated for 5 days & Cy dose was 120mg/kg IV over 4 days. Both cohorts underwent allo-PBSCT at Nasser Institute Hospital, Cairo, between 1997-2010 (TBI group) and 2010-2017 (BU group) (Table1). All patients received graft-versus-host disease (GVHD) prophylaxis using cyclosporine-A (3mg/kg/day IV) from day -1 and methotrexate (15 mg/m2 IV) on day + 1 then 10 mg/m2 IV on days +3, +6 and +11. Post-transplant neutrophil and platelet engraftment were defined by three successive days with absolute neutrophilic count >=1x 109/L and platelet count >=20 x 109/L (without transfusion).Results:In the TBI arm, median time to neutrophil and platelet engraftment was 15 days (9-22) and 15 days (7-47), respectively vs. 14 days (10-22) and 12 days (10-21), respectively in the BU arm. 11/45 TBI patients (24.4 %) developed grade ≥2 acute-GVHD vs. 7/33 (21.2%) patients in the BU arm. Extensive cGVHD was reported in 8/45 (17.7 %) TBI arm vs. 6/33 (18%) patients in the BU arm. Limited cGVHD occurred in 5/45 (11.1%) TBI patients vs. 3/33 (9%) in the BU arm. Cumulative survival was 42.2 % and 15 months OS was 36.7% in the TBI arm vs. 63.6 % and 51.3 % in the BU arm (p= 0.02) (Figure 1). The incidence of sepsis and aGVHD as a cause of transplant related mortality (TRM) were significantly higher in the TBI arm vs. BU arm (p<0.001) (Table 2).Conclusions: Preliminary data demonstrates thatoutcome of BU/Cy is comparable to TBI/Cy as MAC regimen for Allo SCT inadult ALL. With limitation of resources, standard and high risk ALL patients may benefit from allo PBSCT using irradiation-free conditioning regimen associated with lower incidence of sepsis and aGVHD as a cause of transplant related mortality. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Impact of Novel Targeted Therapies and Cytogenetic Risk Groups on Outcome After Allogeneic Transplantation for Adult ALL

Novel high-risk groups have recently been identified in adult acute lymphoblastic leukemia (ALL), including Philadelphia-like, therapy-related, and measurable residual disease after induction therapy. Furthermore, modern targeted therapies have recently been incorporated into ALL management; rituximab for CD20-positive and blinatumomab for measurable residual disease after induction therapy or relapsed or refractory disease. Allogeneic hematopoietic cell transplantation (allo-HCT) is recommended as consolidation therapy for high-risk ALL; however, its relative benefit for these high-risk groups and after novel therapies is unclear. We performed an analysis of posttransplantation outcomes in a cohort of 261 consecutive patients who underwent allo-HCT for ALL at the 3-site Mayo Clinic Cancer Center (January 1, 2008-December 31, 2018). With a median (range) follow-up of 22.4 months (0.5-135.0), the 100-day and 5-year cumulative incidences of nonrelapse mortality rates were 6.5% and 26.7%, respectively. The 5-year cumulative incidences of relapse and death were 22.6% and 46.2%, respectively. The 1-year estimate of the composite endpoint of graft-versus-host disease/relapse-free survival was 39.3%. We observed no associations of novel high-risk groups or modern targeted therapies with overall survival, nonrelapse mortality, or relapse in multivariable analysis. An increased risk of relapse was observed with T-ALL (hazard ratio, 2.16; 95% confidence interval, 1.14-4.09; P=.02) and hypodiploidy/near-triploidy (hazard ratio, 2.84; 95% confidence interval, 1.06-7.62; P=.04). Our analysis suggests that novel high-risk groups derive a similar benefit from allo-HCT as traditional high-risk adult ALL and that novel targeted therapies do not seem to independently predict for posttransplantation outcomes. It also calls for further exploration of maintenance strategies after Allo-HCT to prevent relapse in high-risk subgroups.

The Impact of Low-Dose Cranial Boost on the Long-Term Outcomes of Adult Patients with High-Risk Acute Lymphoblastic Leukemia Undergoing Total Body Irradiation and Allogeneic Hematopoietic Stem Cell Transplantation

PurposeTotal body irradiation (TBI) is an integral part of the conditioning regimen for patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic, hematopoietic, cell transplantation (allo-HCT). There are conflicting data in the literature regarding the utility of a cranial irradiation boost in high-risk adult ALL without evidence of preexisting central nervous system (CNS) involvement. This study investigates the posttransplant clinical outcomes of patients with high-risk adult ALL undergoing TBI conditioning for allo-HCT with or without a whole-brain boost, without overt CNS involvement at the time of diagnosis. Methods and materialsA retrospective cohort study was conducted using a medical record analysis. We identified 58 patients who were treated between January 1998 and December 2016, and met our preset inclusion criteria of adults (age >18 years old) who carried a pathologically confirmed diagnosis of CNS-negative, high-risk ALL, who underwent hematopoietic stem cell transplantation with TBI conditioning. A multivariate analysis of correlation between patient outcomes and collected categorical variables was assessed with stepwise Cox logistic regression. Survival analyses were assessed using the Kaplan-Meier technique with a log-rank test. ResultsWith a median follow-up time of 5.3 years, there was a statistically significant improvement in actuarial 7-year CNS relapse-free survival (100% vs 76.4%; P = .043) in favor of patients undergoing a cranial boost. There was no statistically significant improvement in 7-year progression-free survival (78.3% vs 62.5%; P = .076) or overall survival (49.4% vs 43.5%; P = .921) with versus without a cranial boost. On multivariate analysis, the presence of a cranial boost was the only identified variable with an independent relationship to CNS relapse-free survival. ConclusionsAdult patients with high-risk, CNS-negative ALL were found to have a statistically significant improvement in CNS relapse-free survival and a trend toward improved progression-free survival with the inclusion of a cranial boost with TBI pretransplant conditioning. Our data indicate that further investigation into the use of cranial boost in this patient population is warranted.

Impact of Chronic Graft-Versus-Host Disease on Long-Term Outcomes of Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Adults with High-Risk Acute Lymphoblastic Leukemia in First Remission

Background : The role of reduced-intensity conditioning allogeneic hematopoietic cell transplantation (RIC-HCT) in adult acute lymphoblastic leukemia (ALL) remains unclear because the interpretation of transplantation outcome is mainly limited by the small sample size, short follow-up duration, various regimens for conditioning and graft-versus-host disease (GVHD) prophylaxis, and the heterogeneity of the criteria used to select patients for RIC-HCT. Previously, we conducted a phase 2 trial of RIC-HCT in adults with high-risk ALL who were ineligible for myeloablative conditioning and showed the potential role of this strategy, especially in patients in first complete remission (CR1). Here, we report the long-term outcomes of RIC-HCT by analyzing 122 consecutive adults with high-risk ALL in CR1, particularly focusing on the prognostic relevance of chronic GVHD.Methods: During the period between 2000 and 2014, 122 patients in CR1 (median age, 52 years [range, 15-65 years]; 54 Ph-negative ALL and 68 Ph-positive ALL) were given an identical RIC regimen consisting of fludarabine (150 mg/m2 in total) and melphalan (140 mg/m2in total). The indications for RIC-HCT were advanced age (≥50 years; n=79; 64.8%) and comorbid conditions (n=43; 35.2%). Graft sources were peripheral blood stem cells (n=118; 66 matched sibling donor, 23 matched unrelated donor, 29 mismatched unrelated donor) and bone marrow (n=4; 1 matched sibling donor, 1 matched unrelated donor, 2 mismatched unrelated donor). The median time to transplantation was 155.5 days (range, 103-291 days). GVHD prophylaxis was attempted by administering calcineurin inhibitors (cyclosporine for sibling donor transplants, tacrolimus for unrelated donor transplants) plus methotrexate. Antithymocyte globulin was administered to the patients who received mismatched unrelated donor grafts. If residual leukemia was detected in the absence of GVHD at 3 months after transplantation, calcineurin inhibitors were rapidly discontinued.Results: The median time for neutrophil and platelet recovery was 12 days (range, 8-30 days) and 13 days (range, 5-60 days) after RIC-HCT. Sixty-two patients developed acute GVHD (53 grade II, 5 grade III, 4 grade IV). The cumulative incidence of acute GVHD at 1 year was 50.8% (42.6% for Ph-negative and 57.4% for Ph-positive, P=0.152). Except for 11 patients with early deaths within 100 days, 77 developed chronic GVHD (30 mild, 29 moderate, 18 severe), resulting in a 5-year cumulative incidence of 63.6% (69.1% for Ph-negative ALL and 58.8% for Ph-positive ALL, P=0.319). The median time to onset of chronic GVHD was 140 days (range, 37-843 days) after transplantation. Cytomegalovirus reactivation >10,000 copies/mL was observed in 40.2% (44.4% for Ph-negative ALL and 36.8% for Ph-positive ALL, P=0.447). After a median follow-up duration of 57.9 months (range, 17.7-206.8 months), the 5-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 27.5% (23.9% for Ph-negative ALL and 30.2% for Ph-positive ALL) and 19.0% (17.4% for Ph-negative ALL and 20.3% for Ph-positive ALL), respectively, and the 5-year disease-free survival (DFS) and overall survival (OS) rates were 53.5% (58.4% for Ph-negative ALL and 49.7% for Ph-positive ALL) and 59.8% (60.2% for Ph-negative ALL and 59.3% for Ph-positive ALL). In multivariate analysis, the presence of chronic GVHD lowered CIR (HR, 0.23; 95% CI, 0.10-0.48; P<0.001), but severe chronic GVHD increased NRM (HR, 8.76; 95% CI, 3.39-22.6; P<0.001). Thus, the presence of mild to moderate chronic GVHD was closely related to better outcomes in terms of DFS (HR, 0.45; 95% CI, 0.32-0.64; P<0.001) and OS (HR, 0.44; 95% CI, 0.30-0.64; P<0.001) in all patients as well as in both subgroups of patients. In Ph-positive ALL subgroup of patients, patients without achievement of major molecular response until the time of transplantation had also significantly higher CIR (HR, 7.42; 95% CI, 3.04-18.10; P<0.001) and poorer DFS (HR, 3.47; 95% CI, 1.48-8.14; P=0.004) and OS (HR, 2.58; 95% CI, 1.03-6.47; P=0.043).Conclusion: Our long-term follow-up data with a uniform treatment strategy suggest that RIC-HCT is a valid alternative choice for providing a long-term disease control for adult high-risk ALL patients in CR1. Minimal residual disease-based treatment strategies to reduce leukemia cell burden before HCT and to enhance the graft-versus-leukemia effect are needed in the future. DisclosuresKim:ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lee:Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Low-dose cranial boost in high-risk adult acute lymphoblastic leukemia patients undergoing bone marrow transplant

PurposeAcute lymphoblastic leukemia (ALL) has a predilection for CNS involvement. Patients with high-risk ALL are often managed with transplant using a radiation-based conditioning regimen. Historically, a high-dose prophylactic cranial boost (CB) of ≥12 Gy was given to reduce risk of central nervous system (CNS) recurrence. However, the use of CB has fallen out of favor because of toxicity concerns. In high-risk adults undergoing transplant at our institution, we have used a low-dose 6 Gy CB to reduce toxicity while conditioning adults with fully developed brains. The safety, efficacy, and utility of a low-dose CB in adults are poorly studied; herein, we report their outcomes and toxicity. Methods and materialsWe identified all high-risk ALL patients undergoing total body irradiation as part of their conditioning regimen. Those who received 6 Gy CB or no CB were included (55 total). Their charts were reviewed and statistical analyses were completed with R, version 2.15.2. ResultsIn patients undergoing CB, 3-year CNS disease-free survival and overall survival were 94.7% and 62.7%. In those not undergoing CBs, survivals were 81.8% and 51.5%. Notably, within the CB cohort, patients without prior CNS involvement had no CNS failures. In contrast, in the non-CB cohort, there were 2 CNS failures in patients with no history of CNS involvement. In the CB cohort, the only notable acute toxicity was parotitis (2.8%). Late toxicity in the CB cohort included 1 instance of cataracts (2.8%) without any evidence of cognitive impairment or potential radiation induced secondary malignancy. ConclusionsA dose of 6 Gy CB is well-tolerated in the adult ALL population as part of a radiation-based conditioning regimen. Low-dose CB may be considered in adult patients with high-risk ALL without prior CNS involvement to reduce the likelihood of recurrence.

Post-Remission Treatment with Chemotherapy or Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT) of High-Risk (HR) Philadelphia Chromosome-Negative (Ph-neg) Adult Acute Lymphoblastic Leukemia (ALL) According to Minimal Residual Disease (MRD). Preliminary Results of the Pethema ALL-HR-11 Trial

▪Introduction: Recent studies have shown that young to middle-aged adults who receive a pediatric-inspired chemotherapy regimen for treatment of Ph-neg ALL do not appear to require an alloHSCT if they achieve good response on MRD testing after induction therapy. Patients (pts) who are not good MRD responders achieve better outcomes with alloHSCT than their counterparts who do not receive alloHSCT. However, it is not clear if this approach can be translated to adult ALL pts with HR features at baseline. The aim of the prospective ALL-HR-11 trial from the Spanish PETHEMA Group was to evaluate the response to a differentiated post-induction therapy (chemotherapy or alloHSCT) according to MRD levels (assessed by 8-color, centrally-performed flow cytometry at the end of induction-week 5- and consolidation therapy-week 17-) in HR Ph-neg adult ALL patients. Patients and methods: HR ALL included one or more of the following parameters at baseline: age 30-60 yr, WBC count >30x109/L for B-cell precursor ALL or >100x109/L for thymic T-ALL, pro-B, early or mature T-ALL, 11q23 or MLL rearrangements or complex karyotype. Induction therapy included vincristine, prednisone, daunorubicin and asparaginase (E coli native or PEG according to center availability) for 4 weeks (Induction-1). FLAG-Ida was administered as intensified induction (Induction-2) in pts not achieving CR or those in CR with MRD≥0.1% at the end of induction. For pts in CR and MRD<0.1% early consolidation therapy included 3 cycles with rotating cytotoxic drugs with high-dose methotrexate, high-dose ARA-C and high-dose asparaginase (E coli native or PEG). These pts continued with delayed consolidation (identical to that of early consolidation) followed by maintenance therapy up to 2 yr. in CR if MRD levels after consolidation were <0.01%, otherwise they were assigned to alloHSCT. Pts in CR after Induction-2 received one consolidation cycle and were assigned to alloHSCT. Results: On June 2015, 115 HR ALL pts were evaluable [mean (SD) age 38(13) yr, 67 males, 80/114 precursor B-ALL, 34/114 T-ALL, WBC count 56(96) x109/L]. Results of Induction-1: therapy-related death: 4(4%), resistance: 11 (10%), CR: 95(86%). MRD<0.1% at the end of induction was observed in 75% of CR patients. Induction-2 was administered to 33 patients (no CR: 11, CR and MRD≥0.1%: 22). No differences in the CR rate or in the rate of MRD clearance after induction were observed according to the type of asparaginase administered, although significantly increased hepatic toxicity in consolidation was observed in patients treated with PEG-asparaginase. The 2-yr DFS and OS probabilities for whole series were 51%±18% and 62%±13%. By intention-to treat after Induction-1 36 pts were assigned to alloHSCT and 68 to delayed consolidation and maintenance. The 2-yr DFS and OS probabilities were 54%±25% and 49%±20%, respectively, for pts assigned to alloHSCT, and 50%±22% and 73%±17%, respectively, for those assigned to chemotherapy (P =0.002 for OS comparison). Patients with MRD<0.1% at the end of induction and <0.01% at the end of consolidation (n=51) showed a 2-yr DFS and OS of 55%±25% and 81%±18%, respectively. Conclusions: The preliminary results of this trial, in which the post-induction therapy decision is only based on MRD results, suggest that in HR, Ph-neg adult ALL pts with adequate MRD response after induction and after consolidation the results of therapy are not hampered by avoiding alloHSCT. Supported by grants RD12/0036/0029 (RTICC, FEDER), PI14/01971 FIS, Instituto Carlos III, and SGR225 (GRE), Spain DisclosuresNo relevant conflicts of interest to declare.

Long-Term Outcomes after Myeloablative Allogeneic Hematopoietic Cell Transplantation for Adult Acute Lymphoblastic Leukemia

Allogeneic hematopoietic cell transplantation (alloHCT) is a curative therapy for high-risk acute lymphoblastic leukemia (ALL). However, long-term outcomes after alloHCT for adult ALL have not been well described. We conducted a retrospective cohort study of 72 consecutive adult ALL patients who underwent a first myeloablative alloHCT at our institution from January 2000-December 2013. Median age at HCT was 38 yrs (range, 18-62), 40 (56%) were male, 18 (38%) had high HCT CI score, 14 (19%) had prior CNS leukemia and 35 (49%) had BCR-ABL+ disease. Donor source was HLA-matched related donor for 50% patients and 90% received PBSC as graft source. All patients were transplanted in CR (72% were in 1st or 2nd CR) and 92% received T-cell replete grafts. Median time from diagnosis to alloHCT was 5 months (range, 2-90). The incidences of grade II-IV and III-IV acute GvHD, chronic GvHD and extensive chronic GvHD were 43%, 13%, 51% and 36%, respectively. The median follow-up for our cohort is 76 months. At 6 years after HCT, probability of overall survival (OS) was 33% (95% CI, 21-44%) and relapse-free survival (RFS) was 30% (95% CI, 19-42%), and the cumulative incidence of relapse was 36% (95% CI, 25-48%) and non-relapse mortality (NRM) was 37% (95% CI, 26-49%). The most common causes of death were relapse (43%) and infection (21%); majority of relapses occurred within the first 2-years post-transplantation. There were no second cancer related deaths. In multivariable analyses, factors significantly associated with OS were HCT CI score (HR 2.69 for high vs. low/int., P=0.002) and CMV status (HR 2.62 for donor+ vs. others, P=0.05). HCT CI score was the only predictive factor for RFS (HR 2.26 for high, P=0.007). We also compared outcomes by BCR-ABL status. BCR-ABL+ patients were older (median age 42 vs. 36 yrs, p=0.02), had low HCT CI score (34% vs 22%, p=0.01), were more likely to be in CR1 (74% vs. 32%, p=0.002), and as a result, proceeded to HCT sooner after diagnosis (median 4 vs 7 months, p=<0.001). For BCR-ABL+ and BCR-ABL- patients, 6 year OS was 41% and 25%, RFS was 40% and 21%, relapse was 27% and 45% and NRM was 38% and 36% (P=NS for all comparisons). Myeloablative alloHCT can provide long-term survival for selected high-risk adult ALL patients. Relapses are relatively uncommon after 2 years post-transplant. Long-term NRM is high in this population and we did not observe a plateau in its incidence until 7.5 years post-transplant, suggesting the need for long-term follow up to prevent and manage late complications of alloHCT. [Display omitted] DisclosuresMajhail:Gamida Cell Ltd.: Consultancy; Anthem Inc.: Consultancy.

Detection and management of minimal residual disease in acute lymphoblastic leukemia.

The detection of minimal residual disease (MRD) has become part of the state-of-the-art diagnostics to guide treatment both in pediatric and adult acute lymphoblastic leukemia (ALL). This applies to the treatment of de novo and recurrent ALL. In high-risk ALL, MRD detection is considered an important tool to adjust therapy before and after hematopoietic stem cell transplantation. Precise quantification and quality control is instrumental to avoid false treatment assignment. A new methodological approach to analyzing MRD has become available and is based on next-generation sequencing. In principle, this technique will be able to detect a large number of leukemic subclones at a much higher speed than before. Carefully designed prospective studies need to demonstrate concordance or even superiority compared with those techniques in use right now: detection of aberrant expression of leukemia-specific antigens by flow cytometry of blood or bone marrow, or detection of specific rearrangements of the T-cell receptor or immunoglobulin genes by real-time quantitative polymerase chain reaction using DNA of leukemic cells. In some cases with known fusion genes, such as BCR/ABL, reverse transcriptase-polymerase chain reaction has been used as additional method to identify leukemic cells by analyzing RNA in patient samples. MRD detection may be used to modulate treatment intensity once it has been demonstrated at well-defined informative checkpoints that certain levels of MRD can reliably predict the risk of relapse. In addition, MRD is used as end point to determine the activity of a given agent or treatment protocol. If activity translates into antileukemic efficacy, MRD may be considered a surrogate clinical end point.

Allogeneic Stem Cell Transplantation In Adults With High Risk Acute Lymphoblastic Leukemia (ALL) In 1. Remission (CR1): Promising, But Strongly Influenced By ALL Subtypes

Stem cell transplantation (SCT) has contributed to improved overall survival particularly in high risk adult ALL patients and the indication for SCT is a matter of ongoing discussion. We report the results obtained over a period of 18 years in a large center. Patients received first line treatment according to three consecutive trials of the German Multicenter Study group for Adult ALL (GMALL) and risk stratification was performed accordingly. In the most recent trial patients with high risk and very high risk factors are candidates for allogeneic stem cell transplantation (SCT) in CR1 from matched sibling or unrelated donors. The risk factors are: very high risk (VHR): Philadelphia chromosome positive ALL (Ph+ALL); high risk group (HR) of B-lineage ALL (HR-B): leukocytes > 30/nl at diagnosis and/or delayed CR > 3 weeks (other B) or pro B-ALL and of T-lineage ALL (HR-T): early-T-All and mature T-ALL. In addition standard risk patients were candidates for SCT in case of molecular failure or molecular relapse (SR-Mol). 106 high risk ALL patients in CR1 underwent allogeneic SCT between 1995 and 2012 at our center. Median age was 38 years (17 – 67). 40/106 patients had Ph+ALL (VHR), 57/106 patients were HR patients (HR-B n = 32: pro-B-ALL n = 15, other B n = 17; HR-T n = 25: early T n = 17, mature T n = 4, thymic n = 4). 9/106 patients belonged to the SR-Mol group. Stem cell donors were matched related donors (MRD) in 42 patients and compatible unrelated donors in 64 patients. The conditioning regimen was 12 Gy TBI ± Cyclophosphamide or VP16 in 86 patients, other n = 1, and in patients > 55 years 8 Gy TBI + Fludarabine (n = 5) or Fludarabine + Busulfan (n = 14). ATG as GvHD and rejection prophylaxis was given since 5/2005 in all patients with unrelated SCT and in reduced intensity conditioning regimens (RIC). Results60/106 (57 %) patients with high risk ALL transplanted in CR1 are alive, 46/106 (43 %) patients are dead. The median follow-up of the surviving patients is 64 months (5 – 172). Causes of death were leukemia in 16/106 patients (15%) and transplant-related mortality (TRM) in 30/106 patients (28%), mainly infections ± GvHD (n = 24), secondary malignancies (n = 2) and other (n = 4). In Ph+ALL 19/40 patients (47 %) are alive in CR (CCR), 12/40 are dead due to TRM and 9/40 due to leukemia. In HR-B ALL 23/32 patients (71 %) are in CCR, 8/32 are dead due to TRM and 1/32 due to leukemia. In HR-T ALL 11/25 patients (44 %) are in CCR, 10/25 died due to TRM and 4/25 due to leukemia. In SR-Mol patients 7/9 patients (77 %) are in CCR, 2/9 died due to leukemia. Probability of survival (OS) for all patients at 96 months is 0.48, probability of disease free survival (DFS) at 96 months is 0.47, probability of TRM at 96 months is 0.34. OS was 0.50 for patients with myeloablative conditioning (MAC) (n = 86) and 0.38 for patients with RIC (n = 19), n.s. OS was different for the 4 risk groups: VHR 0.42, HR-B 0.67, HR-T 0.27, SR-Mol 0.74, but not significant (0.095). DFS: VHR 0.42, HR-B 0.68, HR-T 0.24, SR-Mol 0.76 (0.041) and TRM: VHR 0.34, HR-B 0.26, HR-T 0.58, SR-Mol 0. (0.026). In HR-B OS was better for pro-B-ALL than other B-lineage (0.73.vs. 0.66, resp.). OS was lower in early-T-ALL (0.24). In mature T-ALL 3/4 patients are dead, in thymic ALL 1/4 patients. In ConclusionLong term survival and probably cure can be reached in high risk ALL patients after allogeneic stem cell transplantation in CR1. OS in pro-B-ALL and B-lineage-HR-ALL patients is better than in Ph+ALL or in HR-T-ALL due to lower relapse rate and lower TRM. Whether the quality of remission before allogeneic SCT could be improved in Ph+ALL and HR-T-ALL, has to be studied. Allogeneic SCT in SR with molecular failure or relapse show promising data, though in a small patient cohort. For all patients the TRM-rate due to GvHD and infection has to be improved due to better supportive care. Disclosures:No relevant conflicts of interest to declare.

Comparable long‐term outcomes after reduced‐intensity conditioning versus myeloablative conditioning allogeneic stem cell transplantation for adult high‐risk acute lymphoblastic leukemia in complete remission

The role of reduced-intensity conditioning (RIC) in adult acute lymphoblastic leukemia (ALL) remains unclear because of the small sample size, short follow-up duration, various regimens for conditioning and graft-versus-host disease (GVHD) prophylaxis, and the heterogeneity of selection criteria for transplantation. We compared long-term outcomes of 60 consecutive RIC transplants (fludarabine plus melphalan) with 120 myeloablative conditioning (MAC) transplants (total body irradiation plus cyclophosphamide) for adult high-risk ALL in first or second complete remission. All transplants received a uniform strategy of pretransplant chemotherapy and GVHD prophylaxis. Compared to MAC transplants, RIC transplants had older age (46 years vs. 33 years, P < 0.001) and higher proportions of transplantation using peripheral blood (93.3% vs. 13.3%; P < 0.001) but otherwise showed similar characteristics. After a median follow-up of 67 months, RIC transplants showed comparable nonrelapse mortality (21.2% vs. 24.3%) and disease-free survival (50.8% vs. 54.9%) to MAC transplants, although relapse risk was higher (34.2% vs. 26.4%; HR, 2.07; P = 0.019) in multivariate analysis. Other independent factors associated with better outcomes were the presence of chronic GVHD and transplantation in first complete remission. Interestingly, the negative impact of RIC on relapse risk was seen only for Philadelphia-positive ALL transplants (32.7% vs. 19.6%; HR, 3.46; P = 0.020), while no difference was found between RIC and MAC for Philadelphia-negative ALL transplants (35.0% vs. 32.1%; HR, 1.39; P = 0.429). RIC can be considered as a reasonable choice for providing a sufficient long-term graft-versus-leukemia effect for adult high-risk ALL patients ineligible for MAC.

Allogeneic Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia In First Complete Remission: A Systematic Review and Meta-Analysis

AbstractAbstract 3511 Background:While multi-agent induction chemotherapy produces impressive complete remission rates, long term survival remains elusive for most patients with adult acute lymphoblastic leukemia (ALL). Consolidation chemotherapy, autologous hematopoietic cell transplantation (HCT), and allogeneic HCT represent potential treatment alternatives for post-remission therapy, but there is genuine uncertainty regarding the optimal approach. Objectives:To synthesize evidence from all existing randomized controlled trials with a donor vs. no donor comparison in adults with ALL in first complete remission. Our objectives were to determine whether or not there is a survival advantage with allogeneic HCT for ALL in CR1, and also to discern the benefit of this therapy according to disease risk subgroups. Search methods: A broad search of the Medline and Embase electronic databases was performed along with hand search of literature cited in relevant primary articles, search of abstracts from American Society of Hematology and American Society of Clinical Oncology meetings, as well as consultation with content experts in the field. Selection criteria: Include trials were those consisting of adults with ALL in CR1, and prospective randomized controlled trial (RCT) design with ‘genetic randomization’ (i.e. based on availability of matched sibling donor vs. not). Data collection and analysis: Data from relevant trials was abstracted and reviewed by two investigators independently. We extracted data on benefits (OS, PFS) and harms (treatment related mortality, relapse) of compared treatments. Time-to-event data (OS, PFS) were reported as hazard ratios (HR) and dichotomous data (relapse and NRM) were reported as risk ratios (RR). The summary results from each study were pooled under a random effects model. Heterogeneity was assessed both by visual inspection of the forest plots for each outcome, as well as by formal statistical testing for heterogeneity using the chi square and I2 test. Subgroup analyses were performed for disease risk categories. Sensitivity analyses were performed according to domains of methodological quality. Results:A total of 14 relevant trials were identified, consisting of a total of 3215 patients. There was a statistically significant overall survival advantage in favor of the donor vs. no donor group HR of 0.79 (95% CI 0.7 – 0.90; p = 0.0003). The following was observed according to disease risk: standard risk ALL (HR of 0.62 (95% CI 0.46 – 0.84), p = 0.002); high risk ALL (HR of 0.8 (95% CI 0.63 – 1.01), p = 0.06). There was also a statistically significant improvement in disease-free survival in the donor vs. no donor group HR of 0.78 (95% CI 0.66 – 0.92), p = 0.003. Those in the donor group realized a statistically significant reduction in primary disease relapse, RR 0.54 (95% CI 0.4 – 0.73), p < 0.0001, but at the cost of statistically significant increase in non-relapse mortality, RR 2.8 (95% CI 1.66 – 4.73; p = 0.001). There were no significant subgroup differences or heterogeneity demonstrated in sensitivity analyses according to methodological quality domains. Conclusion:The results of this systematic review and meta-analysis support matched sibling donor allogeneic hematopoietic cell transplantation as the optimal post-remission therapy in adults age greater than or equal to 15. This therapy offers superior overall survival, disease-free survival, significantly reduces the risk of disease relapse, but does impose an increased risk of non-relapse mortality. These data importantly are based on adult ALL treated with largely total body irradiation-based myeloablative conditioning, and, therefore, can not be generalized to pediatric ALL, alternative donors including HLA mismatched or unrelated donors, or reduced toxicity or non-myeloablative conditioning regimens. [Display omitted] Forrest plot of overall survival according to donor vs. no-donor status. Disclosures:No relevant conflicts of interest to declare.

Treatment of High-Risk (HR) Philadelphia Chromosome-Negative (Ph-) Adult Acute Lymphoblastic Leukemia (ALL) According to Baseline Risk Factors and Minimal Residual Disease (MRD). Results of the PETHEMA ALL-AR-03 Trial Including the Use of Propensity Score (PS) Method to Reduce Assignment Bias.

Abstract 322 Introduction:Current therapeutic protocols for adult ALL consider MRD together with the baseline risk factors (age, WBC count, immunophenotype, cytogenetics) and speed in response to therapy for treatment decisions. On the other hand, the systematic use of allogeneic SCT for all adult patients (pts) with Ph- HR-ALL is still a matter of debate. The aim of the prospective study ALL-AR-03 from the Spanish PETHEMA Group was to evaluate the response to a differentiated therapy (chemotherapy or allogeneic SCT) according to early bone marrow blast clearance (<10% blasts in bone marrow assessed on day 14) and MRD levels (assessed by cytofluorometry at the end of induction –week 5- and consolidation therapy –week 17-) in HR Ph- adult ALL patients. Patients and methods:HR ALL included one or more of the following baseline parameters: age 30–60 yr, WBC count >25×109/L and 11q23 or MLL rearrangements. Induction therapy included vincristine, prednisone and daunorubicin for 4 weeks. In pts with slow cytologic response to therapy intensified induction with high dose ARA-C and mitoxantrone was administered. Early consolidation therapy included 3 cycles with rotating cytotoxic drugs including high-dose methotrexate, high-dose ARA-C and high-dose asparaginase. Pts. with slow cytologic response on d14 or MRD level >0.05% after consolidation were assigned to allogeneic SCT (related or unrelated) and those with standard cytologic response on d14 and MRD level <0.05% after consolidation received 3 additional cycles of delayed consolidation (identical to those of early consolidation) followed by maintenance therapy up to 2yr in CR. Results:On June 2009, 235 HR ALL pts were evaluable [mean (SD) age 37(14) yr, 129 males, 155 precursor B-ALL, 80 T-ALL, WBC count 64(96) ×109/L]. Induction death: 20(8%), resistance: 11 (5%), CR: 202 (87%). Slow cytologic response on d14 was observed in 137/186 (74%) pts, MRD<0.1% at the end of induction was observed in 70% of CR patients and MRD<0.05% was shown in 82% of pts at the end of consolidation. By intention-to treat allogeneic SCT was assigned to 51 pts and delayed consolidation and maintenance to 107 pts. 4-yr DFS and OS probabilities were 40±15% and 49±15%, respectively, for pts assigned to SCT and 49±13% and 64±12%, respectively, for those assigned to chemotherapy. For OS the Cox model including PS showed that patients assigned to allogeneic SCT had a risk of death of 1.27 (95%CI 0.68–2.37) compared to that of the pts assigned to chemotherapy. Patients with MRD<0.1% at the end of induction and <0.05% at the end of consolidation showed a 4-yr DFS and OS of 54±16% and 77±12%, respectively vs. 31±29% and 38±32%, respectively for those with MRD≥0.1% after induction and ≥0.05% after consolidation (p=0.04 and 0.006, respectively). By multivariate analysis, including the type of treatment as covariate, age and slow cytologic response were the prognostic factors for CR, MRD level was associated with DFS, and MRD level and WBC count were the main parameters with influence on OS. Conclusions:These results suggest that in HR Ph- adult ALL pts with adequate response to induction and adequate clearance of MDR after consolidation the results of therapy are not hampered by avoiding allogeneic SCT. MRD is the main prognostic factor for CR, DFS and OS. Supported by grants P-EF/07 from FIJC and RD 06/0020/10556 from RETICS, and PI051490 from FIS, Instituto Carlos III. Disclosures:No relevant conflicts of interest to declare.

Status of Minimal Residual Disease Determines Outcome of Autologous HSCT in Adults with High-Risk Acute Lymphoblastic Leukemia.

Abstract 2321Poster Board II-298The role of autologous hematopoietic stem cell transplantation (autoHSCT) in the treatment of adult acute lymphoblastic leukemia (ALL) is a subject of controversies as several prospective studies failed to prove its advantage over maintenance chemotherapy. Those studies, however, did not take into account the status of minimal residual disease (MRD), which is now recognized a potent predictor for relapse among patients treated with conventional-dose chemotherapy. The goal of this analysis was to determine the impact of MRD on outcome of autoHSCT.Data on 123 autoHSCT recipients collected from 6 study groups cooperating in the European Leukemia Net were analyzed. Median age of 77 B-lineage and 46 T-lineage high-risk ALL patients was 31 (16-59) years. Ph+ ALL was recognized in 20 cases. All patients were in first complete remission (CR) lasting 6 (1.5-22) months. Peripheral blood was used as a source of stem cells in 67 patients whereas bone marrow, in 56 cases. Conditioning was based on chemotherapy alone (n=76) or total body irradiation (n=47). MRD was evaluated in bone marrow with the use of either multiparametric flow cytometry (n=79) or molecular techniques (n=44). MRD level of 0.1% bone marrow cells was used as a cut-off point for the purpose of this study. At the time of autoHSCT MRD was &0.1% in 93 patients and ≧0.1% in 30 cases.With the median follow up of 5 years, the probability of leukemia-free survival (LFS) at 5 years for the whole group equaled 48% (+/-5). Three patients died of transplantation-related complications. The LFS rate was significantly higher for patients with the MRD level at transplantation &0.1% compared to those with MRD ≧0.1% (57% vs. 19%, p=0.0002). The difference was particularly pronounced for peripheral blood HSCT (66% vs. 20%, p=0.0006) and for T-lineage ALL (62% vs. 8%, p=0.001). In a multivariate analysis adjusted for other potential prognostic factors (age, CR duration, Ph+ ALL, immunophenotype, source of stem cells, type of conditioning), the MRD status &0.1% remained the only independent factor associated with increased LFS (HR=2.5, p=0.0009).CONCLUSIONS: MRD status is the most important predictor for LFS after autoHSCT in adults with ALL. More than half of patients with high risk disease and low MRD level at the time of transplantation may be cured. This observation may contribute to re-evaluation of the role of autoHSCT in the therapy of adult ALL. Disclosures:No relevant conflicts of interest to declare.

New Definition of Treatment Response in Adult Acute Lymphoblastic Leukemia (ALL): Use of Molecular Markers for Minimal Residual Disease (MRD).

Abstract 90▪FN2▪This icon denotes an abstract that is clinically relevant.Response to treatment measured by cytologic bone marrow evaluation has been so far the most important prognostic factor in adult ALL, and cytological complete remission (cyCR) and relapse (cyREL) are accepted endpoints for clinical trials. However, measurement of MRD is a more sensitive approach for assessment of response. In the past decade it has been confirmed that MRD is an independent, strong prognostic factor in ALL. The most widely applied method is based on quantative PCR evaluation of individual rearrangements of TCR and Ig genes. Methodology, interpretation and definitions are highly standardised and confirmed in different labs (e.g. van der Velden et al, Leukemia, 2007). Therefore it is essential to define and validate MRD based response criteria – namely complete molecular/complete MRD response (molCR), molecular failure/MRD persistence (molFAIL) and molecular relapse/MRD relapse (molREL) - as endpoints for clinical trials.Since 1999 the German Multicenter Study Group for Adult ALL (GMALL) has conducted two consecutive studies (GMALL 06/99 and 07/2003) with a risk and MRD adapted treatment strategy and prospective MRD evaluation. 1489 evaluable pts (15–55 y) with Ph-negative standard (SR) and high risk (HR) ALL have been included so far. MRD evaluation as described above has taken place in central labs. For analysis of molCR MRD evaluation was restricted to pts with cyCR (prerequisite: at least one marker with sensitivity and quantitative range of minimum 10−4 for negative results). MolCR was defined as negative MRD status after induction therapy. MolREL was defined as reappearance of MRD above 10−4 after achievement of molCR.MolCR after induction: The overall cyCR rate was 89% with differences between SR and HR (92% vs 84%;p<.0001) and age < vs >35 yrs (90% vs 86%;p=.01) but not B vs T-lineage (89% vs 88%). As expected the molCR was lower (69%) in 479 evaluable pts. Significant differences were seen between SR vs HR (77% vs 46%;p<.0001) and B vs T-lineage (63% vs 79%;p=.0005). The most rapid decrease of MRD was observed after induction phase I (34% molCR) and phase II (69%), whereas the effect of first consolidation was limited (72%) indicating a progressive selection of chemotherapy resistant leukemic clones. MolCR evaluation was also used to assess treatment modifications such as asparaginase intensification or addition of rituximab to induction therapy.Prognostic impact of molCR:SR pts were scheduled for chemotherapy. Those with molCR had a superior overall survival (OS) when compared to molFAIL (67% vs 38%;p<.0001) which was mainly due to a lower relapse rate (RR) (26% vs 59%;p<.0001) leading to better remission duration (RD) (57% vs 29%;p<.0001). MolFAIL pts had a better OS with SCT in CR1 than without (60% vs 27%;p=.09).All HR pts were scheduled for SCT in CR1. OS was superior for MolCR vs MolFAIL (66% vs 42%; p=.003). The RR was higher for molFAIL vs molCR on chemotherapy (66% vs 18%;p=.04) and after SCT (34% vs 11%;p=.04). Even after SCT pts with molCR had a better OS (75% vs 58%; p=.03).MolREL: The incidence and outcome of molREL was evaluated in 432 pts with MRD tests during and after treatment. 36 molREL without additional extramedullary relapse were observed. The OS was 36% and the probability of cyREL was 82% with median of 75 d from molREL to cyREL. All pts not treated at molREL relapsed (N=12). Only 1/11 (9%) pts who were transferred to SCT in cyCR1 after additional treatment, including experimental drugs, relapsed compared to 21/25 (84%) pts without SCT in cyCR1 (p<.0001).Overall these data show in the largest cohort of adult ALL pts with MRD analysis reported so far, the proof of principle for molecular response evaluation. In a study with high cyCR rate it allows to detect differences between subgroups and treatment approaches and thereby refines the evaluation of treatment efficacy. It is a clinically relevant endpoint since molFAIL is associated with significantly poorer RD and OS even after subsequent SCT. Detection of molFAIL and molREL identifies pts with resistance to conventional drugs and the need for targeted, experimental drugs and SCT in cyCR1 before occurrence of cyREL. Molecular response evaluation with standardised methods provides new refined endpoints for future trials, including pivotal trials with new drugs with the major advantage of early decision points and strong correlation to clinical outcome.Supported by Deutsche Krebshilfe 702657Ho2 and BMBF 01GI9971/8 Disclosures:No relevant conflicts of interest to declare.

Reduced-Intensity Conditioning followed by Peripheral Blood Stem Cell Transplantation for Adult Patients with High-Risk Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) with high-risk features has a poor prognosis in adults despite aggressive chemotherapy. Reduced-intensity conditioning (RIC) is a lower toxicity alternative for high-risk patients requiring hematopoietic cell transplantation (HCT); however, it has not been widely used for ALL. We conducted a retrospective study of 24 high-risk adult ALL patients who received an RIC regimen of fludarabine (Flu)/melphalan (Mel) prior to allogeneic peripheral blood stem cell transplantation (PBSCT) between 6/14/02 and 6/15/07 at the City of Hope. Indications for the RIC regimen were: (1) aged 50 years or older (42%), (2) compromised organ function (54%), or (3) recipient of a previous HCT (37.5%). Patients had a median age of 47.5 years and the median follow-up was 28.5 months for living patients. Both overall survival (OS) and disease-free survival (DFS) at 2 years was 61.5%. Relapse incidence was 21.1% and nonrelapse mortality (NRM) was 21.5% at 2 years. Chronic graft-versus-host (cGVHD) developed in 86% of evaluable patients. In this series, no significant correlations were made between outcomes and patient age, presence of Philadelphia chromosome, relatedness of donor source, or prior HCT. These high survival rates for high-risk ALL patients following RIC HCT may offer a promising option for patients not eligible for a standard myeloablative transplant.

Treatment of High-Risk (HR) Philadelphia Chromosome-Negative (Ph-) Adult Acute Lymphoblastic Leukemia (ALL) According to Baseline Risk Factors and Minimal Residual Disease (MRD). Results of the PETHEMA ALL-AR-03 Trial.

Background and aim: Current therapeutic protocols for adult ALL consider MRD together with the baseline risk factors (age, WBC count, immunophenotype, cytogenetics) and speed in response to therapy for treatment decisions. On the other hand, the systematic use of allogeneic SCT for all adult patients (pts) with Ph- HR-ALL is still a matter of debate. The aim of the prospective study ALL-AR-03 from the Spanish PETHEMA Group was to evaluate the response to a differentiated therapy (chemotherapy or allogeneic SCT) according to early bone marrow blast clearance and MRD levels (assessed by cytofluorometry at the end of induction and consolidation therapy) in HR Ph- adult ALL patients.Patients and methods: HR ALL included one or more of the following baseline parameters: age 30–60 yr, WBC count >25x109/L and 11q23 or MLL rearrangements. Induction therapy included vincristine, prednisone and daunorubicin for 4 weeks. In pts with slow cytologic response to therapy (≥10% blasts in bone marrow assessed on d14) intensified induction with high dose ARA-C and mitoxantrone was administered. Early consolidation therapy included 3 cycles with rotating cytotoxic drugs including high-dose methotrexate, high-dose ARA-C and high-dose asparaginase. Pts. with slow cytologic response on d14 or MRD level >0.05% after consolidation were assigned to allogeneic SCT (related or unrelated) and those with standard cytologic response on d14 and MRD level <0.05% after consolidation received 3 additional cycles of delayed consolidation (identical to those of early consolidation) followed by maintenance therapy up to 2yr in CR.Results: On June 2008,192 patients were evaluable (mean (SD) age 37(10) yr, 105 males, 119 precursor B-ALL, 73 T-ALL, WBC count 65(99) x109/L). Induction death: 17(9%), resistance: 12 (6%), CR: 163 (85%). MRD<0.1% was observed in 64% of CR patients. Early consolidation was completed in 126 patients. MRD<0.05% was observed in 65% at the end of consolidation. On June 2008, allogeneic SCT was performed to 30 pts (15 from HLA-identical siblings and 15 MUD), TRM 11 pts, relapse 4, CCR 15. Delayed consolidation and maintenance was administered to 79 pts (toxic death 4 pts, relapse 21, CCR 54). Four-yr DFS for the whole series was 36±7% (37±19% for pts assigned to SCT and 56±12% for those assigned to chemotherapy). Slow cytologic response was associated with a lower CR probability and higher induction death. No baseline variable was associated with a higher probability of MRD negativity after induction or consolidation.Conclusions: These results suggest that in HR Ph- adult ALL pts with adequate response to induction and adequate clearance of MDR the results of therapy are not hampered by avoiding allogeneic SCT. Supported by grants P-EF/07 from FIJC and RD 06/0020/1014 from Instituto Carlos III