Prognostic Factors for Survival after Allogeneic Transplantation in Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is a heterogeneous disease and treatment guidelines are still evolving. Allogeneic stem cell transplantation (allo-SCT) offers a potentially curative option and is recommended in first relapse and for high-risk patients in first complete remission (CR). Survival after allo-SCT could be substantially improved due to better risk stratification, patient selection and adapted treatment protocols leading to reduced non-relapse mortality (NRM). Prognostic factors for survival after allo-SCT still need to be defined: pheno- and genotype, patients´ age, conditioning regimens and remission status prior to allo-SCT are under discussion. We analyzed the outcome of 180 consecutive ALL patients who received allo-SCT at the Freiburg University Medical Center between 1995 and 2018 with regard to treatment response, survival, adverse reactions, and performed subgroup analyses to identify prognostic factors. The median age in our cohort was 37 years (ys), 19% were older than 55 ys. 27% were diagnosed with Philadelphia (Ph)-positive ALL, 24% with T-ALL. 36% were treated with relapsed/refractory disease. 48% of allo-SCTs were conducted with a HLA-matched, 19% with a HLA-mismatched unrelated and 33% with a related donor. In 61% the conditioning regimen included total body irradiation (TBI). In 48% no minimal residual disease (MRD) was detected prior to allo-SCT, 20% were transplanted in MRD-positive CR. The overall response rate was 86%, with MRD-negativity in 78%. With a median follow up of 10 ys, we observed a median overall survival (OS) of 23 months and a median progression free survival (PFS) of 11 months. The 10ys-OS was 33%, the 10ys-PFS 31%. The cumulative incidence of relapse was 68% at 10 ys, the cumulative incidence of NRM 12%. Acute graft-versus-host disease (GvHD) III-IV° occurred in 17%, severe chronic GvHD in 9%. Survival was significantly better in patients reaching MRD-negative CR before allo-SCT (10ys-OS 48% vs. 19%, p<0.0001; 10ys-PFS 46% vs. 17%, p<0.001) and in thoses receiving TBI (10ys-OS 40% vs. 19%, p<0.01; 10ys-PFS 37% vs. 19%, p<0.001). There was no significant difference in survival between patients younger or older than 55 ys (10ys-OS 37% vs. 21%, p=0.183; 10ys-PFS 34% vs. 21%, p=0.208) and between those diagnosed with T-, Ph-positive or -negative B-ALL (10ys-OS 41% vs. 35% vs. 29%, p=0.298; 10ys-PFS 38% vs. 33%. vs. 27%, p=0.238). Due to lower NRM, survival improved depending on the year of allo-SCT (10ys-OS 1995-2000 22% vs. 2001-2010 32% vs. 2011-2018 n.r., p<0.01; 10ys-PFS 20% vs. 30% vs. n.r., p<0.01). With a very long follow-up and high rate of MRD-assessment, we observed a high response rate and a low rate of severe GvHD. Our data confirm that allo-SCT enables long-term survival in high-risk ALL, suggest that, in certain subgroups, survival may be best in patients transplanted in CR and receiving TBI for conditioning, including the relevant observation that allo-SCT can be performed in carefully selected elderly patients. Disclosures Finke: Medac: Honoraria, Other: research support, Speakers Bureau; Neovii: Honoraria, Other: research support, Speakers Bureau; Riemser: Honoraria, Other: research support, Speakers Bureau. Wäsch:Pfizer: Consultancy; Sanofi: Other: Travel, Research Funding; Celgene: Other: travel, Research Funding; Jazz: Other: travel, Research Funding; Amgen: Consultancy; Gilead: Consultancy; Sanofi: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Amgen: Other: travel, Research Funding; Gilead: Other: travel, Research Funding.

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Pediatric-Inspired Regimens Are Associated with Better Outcomes When Compared with Hypercvad in Hispanic Adolescents and Young Adults with Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2019-125370 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3877-3877 ◽

Cited By ~ 1

Author(s):

Roberta Demichelis ◽

Karla Adriana Espinosa ◽

Juan Rangel-Patiño ◽

Emmanuel Almanza ◽

Ana Cooke

Keyword(s):

Young Adults ◽

Prognostic Factors ◽

Acute Lymphoblastic Leukemia ◽

High Risk ◽

B Cell ◽

Relapse Rate ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Control Group ◽

Poor Outcomes

Background Acute lymphoblastic leukemia (ALL) is frequent in Mexico, representing 51% of acute leukemia in adults. Hispanic ethnicity is associated with high-risk features and poor outcomes. We previously reported a multicenter experience in Mexico, where the majority of our ALL-patients (67%) were adolescents and young adults (AYA), mostly treated with HyperCVAD and with poor outcomes: 3-year overall survival (OS) of 25.7%. Many groups have demonstrated better outcomes with pediatric-inspired regimens (PIR) in the AYA-group, with long term OS > 60%. In 2016-2017 we changed the standard of care from HyperCVAD to PIR in two of the centers from the previously mentioned study. Methods We included AYA-patients with the diagnosis of Philadelphia-negative ALL treated with PIR (ALL-BFM 90 or CALGB 10403) between March 2016 and June 2019 in two centers in Mexico City. Both regimens were modified from the original: we used E. Coli asparaginase instead of pegaspargase and mercaptopurine instead of thioguanine. We compared these patients with our common historic database of patients with the same characteristics diagnosed between February 2009 and June 2015, treated with HyperCVAD. Hyperleukocytosis was defined as a white blood cell count > 30 x103/mcL for B-cell ALL and > 100 x103/mcL for T-cell ALL. Patients with t(v;11q23), hypodyploid or complex karyotype were considered high-risk. Baseline characteristics of both groups were compared with Chi-square or Mann-Whitney U test. We estimate OS by Kaplan-Meier method and compared groups by log-rank test. Multivariate Cox proportional hazards regression was used to evaluate independent prognostic factors associated with OS. Results We compared 73 patients treated with PIR with a control group of 137 patients treated with HyperCVAD. The patients treated with PIR received either ALL-BFM 90 (N=46) or CALGB 10403(N=27). The median follow-up was 49.8, 23.3 and 12.7 months for HyperCVAD, ALL-BFM 90 and CALGB 10403 respectively. Patients treated with PIR were slightly older than those in the control group (median 24 vs. 20 years, p=0.005) and presented with high-risk karyotype more frequently (31.9% vs. 12.2%, p=0.042). Most of the patients were B-cell ALL (91.8% for PIR and 95.6% for HyperCVAD; p=0.349). Comparing PIR vs. HyperCVAD, there were no differences in the proportion of patients with hyperleukocytosis (33.3% vs. 25.0%, p=0.128) or obesity (24.7% vs. 16.4%, p=0.192). The induction related mortality was 5.7% for the entire group with a trend that favors PIR (1.4% vs. 8.0%, p=0.061). In patients treated with PIR, the 4-week complete remission (CR) rate was higher (79.5% vs. 64.2%, p=0.027) and the relapse rate was lower (41.5% vs. 60.0%, p=0.027). Patients treated with PIR were more frequently treated with allogeneic stem-cell transplant (alloSCT) in first CR: 19.2% vs. 7.3%, p=0.017. The median OS was significantly higher with PIR than with HyperCVAD, with a median of 19.0 months (3.3-25.4 months) vs. 11.1 months (7.3-14.8 months), and a 18-month OS of 53% vs. 33%, p=0.017. When comparing the two different PIR (ALL-BFM 90 vs. CALGB 10403), the patients treated with ALL-BFM 90 had more frequently high-risk karyotypes (46% vs. 10.5%, p=0.012). Both regimens were associated with similar 4-week CR rate (78.3% vs. 81.5%, p=1). OS was higher with the CALGB 10403 with an 18 month-OS of 79% vs. 42% with the ALL-BFM 90 (p=0.044). When adjusted for high-risk karyotype, the benefit on OS was no longer significant. In the multivariate analysis for OS, the independent significant prognostic factors were: treatment with a PIR (HR 0.428, 95% CI 0.221-0.826, p=0.011), alloSCT in first CR (HR 0.316, 95% CI 0.106-0.938, p=0.038) and high-risk karyotype (HR 2.695 95% CI 1.272-5.560, p=0.009). Discussion Although different groups have shown the benefit of PIR in the AYA-patients, the MD Anderson group couldn´t found any benefit from using the augmented BFM when compared to HyperCVAD. In our experience, the outcomes with HyperCVAD are poor in this group. In this report, the treatment with PIR was associated with a higher CR rate, lower relapse rate and better OS when compared with our historical HyperCVAD in AYA-patients. The benefit on survival was independent of other risk factors or alloHSCT. The main limitation of the study is the comparison with a historical group. However, given the general trend to treat these patients with RIP, a prospective randomized study in this regard is unlikely. Disclosures Demichelis: Abbvie: Speakers Bureau; AMGEN: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Shire: Speakers Bureau.

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Frontline Consolidation with Blinatumomab for High-Risk Philadelphia-Negative Acute Lymphoblastic Adult Patients. Early Results from the Graall-2014-QUEST Phase 2

Blood ◽

10.1182/blood-2021-146163 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1232-1232

Author(s):

Nicolas Boissel ◽

Francoise Huguet ◽

Carlos Graux ◽

Yosr Hicheri ◽

Patrice Chevallier ◽

...

Keyword(s):

Stem Cell ◽

Acute Lymphoblastic Leukemia ◽

High Risk ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Cell Transplant ◽

Phase 2 ◽

Early Results ◽

Grade 5

Abstract Introduction: Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) with high-risk genetics and/or measurable residual disease (MRD) are at high-risk of disease recurrence. In the previous GRAALL-2005 study, we identified KMT2A rearrangements (KMT2A-r), IKZF1 intragenic deletion (IKZF1del) and post-induction (TP1, week 6) MRD ≥ 0.01% as independent factors to predict relapse in Ph-negative B-cell precursor (BCP) ALL (Beldjord K, Blood 2014). In the GRAALL-2014 trial, high-risk (HR) patients were thus defined by the presence of at least one of these three factors. Among them, only those with higher MRD levels defined as TP1-MRD ≥ 0.1% and/or week 12 (TP2) MRD ≥ 0.01% were considered at very high risk (VHR) and proposed allogeneic hematopoietic stem cell transplant (alloSCT) in first remission (Dhedin et al., Blood 2015). Since October 2018, all these patients were eligible to be included in the GRAALL-2014-QUEST phase 2 study to receive blinatumomab as part of consolidation and maintenance phases or as a bridge to transplant. Methods: From October 2018 to December 2020, 95 patients with high-risk Ph-negative BCP-ALL without central nervous system involvement at diagnosis and in continuous complete remission after induction and consolidation 1, were prospectively included to start blinatumomab at week 12. One patient was excluded because of T-ALL phenotype (with CD19 aberrant expression). Patients with alloSCT indication and a stem cell source received blinatumomab 28 microg/d administered by continuous intravenous infusion (cIV) until transplant. A minimum of 4 weeks blinatumomab was recommended before proceeding to transplantation. All other patients received 5 cycles of blinatumomab 28 microg/day cIV (for 28 days), during consolidation 2 and 3 and at months 1/3/5 of the maintenance phase respectively. The primary objective was disease-free survival (DFS). Secondary objectives included post-blinatumomab MRD response at TP3 (after consolidation 2 or before alloSCT), overall survival (OS), and safety. Early results are reported here. Results: Median age was 35 years old (range, 18-60). Median white blood cell count (WBC) at diagnosis was 12 G/L (range, 1-449). Oncogenetic analyses allowed classifying ALL as Ph-like (18%), KMT2A-r (17%), DUX4/ERGdel (13%), ZNF384-r (11%), low hypodiploidy/near triploidy (7%), B-other (26%) or unknown (9%). An IKZF1del was found in 37/93 (40%). A TP1-MRD ≥ 0.01% was found in 46/94 patients (49%). Final risk group was HR for 45 patients and VHR for 49 patients. Last pre-blinatumomab MRD was <0.01% in 49/88 (56%) of evaluable patients. A total of 40 patients (42%) received an alloSCT. The median number of blinatumomab cycles received in patients not proceeding to alloSCT was 4 cycles (range, 1-5). Thirty-nine severe adverse events (SAEs) were reported: 1 CRS (grade 2), 8 neurotoxicities (1 grade 2, 3 grade 3, 3 grade 4, 1 grade 5), 19 infections, and 11 others. The only grade 5 SAE occurred after alloSCT (seizures). After blinatumomab, a complete MRD response (with at least 0.01% sensitivity) was achieved in 61/82 (74%) evaluable patients and in evaluable patients with pre-blinatumomab detectable MRD. MRD response to blinatumomab was lower in patients with high pre-blinatumomab MRD level, while not impacted by age, WBC, or oncogenic subgroup. With a median follow-up of 20 months, 18-month DFS and OS was 78.8% (95% CI [66.9-86.8]) and 92.1% (95% CI [83.2-96.4]) respectively (Figure 1). Patients with VHR diseases had a worse DFS (68.8%, 95% CI [51.1-81.2]) as compared to other patients (90.6%, 95% CI [72.1-97.1]); p=0.018). This difference of DFS was abrogated by censoring patients at transplant (VHR 88.1%, 95% CI [65.5-96.3] versus others 90.6%, 95% CI [72.1-97.1%], p=0.10). Other factors significantly associated with better DFS were DUX4/ERGdel subgroup, low pre-blinatumomab MRD, and complete MRD response after blinatumomab. Conclusion. In patients wih high-risk BCP-ALL, blinatumomab added to consolidation is safe and gives promising results. A comparison to similar patients treated in the same GRAALL-2014 study before October 2018 is planned with a longer follow-up. Figure 1 Figure 1. Disclosures Boissel: Novartis: Consultancy, Honoraria, Research Funding; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; SANOFI: Honoraria; Servier: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; CELGENE: Honoraria; JAZZ Pharma: Honoraria, Research Funding; PFIZER: Consultancy, Honoraria. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation. Delabesse: Astellas: Consultancy; Novartis: Consultancy. Dombret: Abbvie: Honoraria; Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; NOVARTIS: Research Funding; pfizer: Honoraria, Research Funding; servier: Research Funding; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. OffLabel Disclosure: Blinatumomab in frontline high-risk acute lymphoblastic leukemia

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Sex-Based Disparities in Outcome in Childhood Acute Lymphoblastic Leukemia (ALL): A Children's Oncology Group (COG) Report

Blood ◽

10.1182/blood-2020-136609 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 38-39

Author(s):

Sumit Gupta ◽

David T. Teachey ◽

Meenakshi Devidas ◽

Zhiguo Chen ◽

Kimberly P. Dunsmore ◽

...

Keyword(s):

Risk Factors ◽

Prognostic Factors ◽

Acute Lymphoblastic Leukemia ◽

Treatment Failure ◽

Cumulative Incidence ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Publicly Traded ◽

Cns Relapse ◽

Standard Risk

BACKGROUND: Survival for children with B and T acute lymphoblastic leukemia (B-ALL, T-ALL) has continued to improve. In past cohorts, boys experienced inferior survival outcomes compared to girls. Though reasons are unknown, previous investigators have suggested that these disparities are explained by imbalances in risk factors, such as a higher proportion of T-ALL among boys. We thus examined whether sex-based disparities persist with modern intensive therapy when adjusted for other risk factors. We also determined if patterns of toxicity and treatment failure varied by sex. METHODS: We identified a cohort of patients age 1-30.99 years enrolled on frontline COG trials for B-ALL (standard risk: AALL0331; high risk: AALL0232) and T-ALL (AALL0434) between 2004-2014. Duration of treatment was sex-dependent, with boys receiving an additional year of Maintenance therapy. A limited number of B-ALL patients (those with slow early response or CNS3 status) underwent cranial radiation, while all intermediate and standard risk T-ALL patients did so. Sex-based differences in the distribution of various prognostic factors were explored, including age at diagnosis, initial white blood cell (WBC) count, central nervous system (CNS) status, leukemia cytogenetics, and end Induction minimal residual disease (MRD). Event-free and overall survival (EFS, OS) were compared between boys and girls using log-rank tests and multivariable Cox regression analyses. Finally, we explored sex-based differences in toxicity rates and in the cumulative incidence of specific causes of treatment failure, including treatment-related mortality (TRM), overall relapse, and subcategories of relapse by site. RESULTS: The study cohort included 8,202 patients with B-ALL [4,463 (54.4%) boys] and 1,562 patients with T-ALL [1,161 (74.3%) boys]. Among B-ALL patients, boys were older than girls and slightly more likely to have unfavorable cytogenetics (Table 1). There was no difference in the distribution of initial WBC or CNS status. Among T-ALL patients, boys were again older than girls, but other prognostic factors did not differ by sex (Table 1). B-ALL boys were less likely to be end induction marrow MRD < 0.01% [3,268 (76.1%) vs. 2791 (78.1%); p=0.04] while T-ALL boys were more likely to achieve end induction MRD < 0.01% [659 (59.0%) vs. 221 (56.8%); p=0.01], although in both cases absolute differences were small. EFS and OS were inferior in B-ALL boys compared to girls (5-year: EFS 84.6%±0.6% vs. 86.4%±0.6%; p=0.003; OS 91.7%±0.4% vs. 92.8%±0.5%; p=0.046). The risk of inferior outcomes among B-ALL boys persisted after adjustment for other prognostic factors in both EFS [hazard ratio (HR) 1.18, 95% confidence interval (1.05-1.33); p=0.003] and OS (HR 1.17 (1.00-1.37); p=0.048). There were no sex-based differences in EFS or OS in T-ALL. When examining specific toxicities and causes of treatment failure, osteonecrosis rates were lower among boys [297/5,624 (5.3%) vs. 281/4,140 (6.8%); p=0.002]. The incidence of TRM did not differ by sex. The incidence of relapse was, however, greater in boys than girls with B-ALL (11.2%±0.5% vs. 9.6%±0.5%; p=0.001). This risk was attributable to a higher incidence of relapses involving the CNS (4.2%±0.3% vs. 2.5%±0.3%; p<0.0001) and in other extramedullary sites, including the testes (1.3%±0.2% vs. 0.7%±0.1%; p= 0.001). Notably, there was no difference in the cumulative incidence of isolated bone marrow relapse (5.4%±0.4% vs. 6.2%±0.4%; p=0.49). Among T-ALL patients, there were no sex-based differences in the cumulative incidence of relapse, either overall or by relapse site. CONCLUSIONS: Small sex-based disparities in ALL outcomes persist despite overall improvements, extended treatment duration, and extra intrathecal therapy in boys. This is mainly attributable to a higher risk of CNS relapse in boys with B-ALL, despite no sex-based differences in initial CNS status, and persists when adjusted for other prognostic risk factors. The lack of sex-based disparities in T-ALL by sex may be in part due to an increased use of CNS radiation, given older studies which observed increases in CNS relapse rates among boys but not girls when radiation was eliminated. Future studies to determine the mechanisms underlying this disparity, including potential sex-based differences in steroid metabolism, are warranted. Disclosures Teachey: Amgen: Consultancy; Sobi: Consultancy; Janssen: Consultancy; La Roche: Consultancy. Dunsmore:Dexcom: Current equity holder in publicly-traded company. Mattano:Melinta Therapeutics: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Borowitz:Amgen: Honoraria. Raetz:Pfizer: Research Funding; Celgene/BMS: Other. Loh:Pfizer: Other: Institutional Research Funding; Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees. Hunger:Novartis: Consultancy; Amgen Inc.: Current equity holder in publicly-traded company, Honoraria.

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Clinical Features and Survival According to Minimal Residual Disease in a Colombian Population Diagnosed with B-Cell Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2021-153874 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4459-4459

Author(s):

Angela María Peña ◽

Sandra Vanesa Rios ◽

Luis Antonio Salazar ◽

Manuel Rosales ◽

Sara Ines Jimenez ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

High Risk ◽

B Cell ◽

Research Funding ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Advisory Board ◽

The Other ◽

Minimal Residual

Abstract Introduction Acute lymphoblastic leukemia (ALL) is a clonal hematopoietic disorder that originates from B or T lymphoid progenitors and has well validated prognostic and predictive factors that influence outcomes. One of the strongest prognostic factors is the detection of minimal residual disease (MRD) which measures residual cell population after treatment when a morphologic complete response has been achieved. MRD positivity is associated with a higher risk of relapse and poor response to chemo or radiotherapy Objectives The aim of the study was to assess the prognostic impact of post-induction MRD status in a cohort of ALL Colombian patients in terms of relapse-free survival (RFS) and overall survival (OS). Methods This is a retrospective observational study conducted at a Colombian university hospital and included a cohort of ALL patients diagnosed between 2013 and 2020 treatment according to protocol PETHEMA (Spanish Program for Hematology Treatments). MRD was measured with 8-color flow cytometry evaluate on bone marrow. MRD status was classified as negative MRD (NMRD) or positive MRD (PMRD) based on a sensitivity threshold of <0,01% or ≥0,01% leukemic cells, respectively, following to international guides. Demographic and clinical characteristics were analyzed using descriptive statistics. Kaplan-Meier method was used to assess overall RFS and OS. Results A total 128 patients were included. The median age at diagnosis was 34 years (range 0-89 years), 54% were men, 26% were overweight, 22% obese, 6.2% had type 2 DM (T2DM), and most had a ECOG PS of £2 (94%). Most patients (80.5%) had high risk according PETHEMA, B-ALL and were classified as ALL-2 (58%) according to FAB classification with Pre-B cell ALL being the most common phenotype (54.7%). Ph+ ALL was diagnosed in 12% of patients. Most used treatments protocols were PETHEMA-AR and PETHEMA-RI in 43.8% and 11.6% of patients, respectively. Post-induction MRD measurement was available in 98 patients, 36 (36.7%) had NMRD and 62 (63.3%) PMRD. From the 36 patients with NMRD, eight patients (22.2%) received Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT): two of them, were transplanted in first complete remission, one because of high risk and the other one for BCR-ABL positivity. The other six patients received alloHSCT in second remission and all of them relapsed after late consolidations. Finally, alloHSCT was done in 28 patients with PMRD (45.2%). The 12-month OS for patients with NMRD was 68.7% (95%CI 50.5-81.2) compared to 63.7% (95%CI 50.3-74.4) in the ones with PMRD, p=0.375. 12-month RFS was 83.3% (95%CI 61.5-93.4) in patients with NMRD and 90.0% (95%CI 72.1-96.7) in patients with PMRD, p=0.436. (Figure 1). OS was significantly higher for the PMRD patients who underwent AlloHSCT 96.4% (95%CI 77.2-99.4) versus not underwent 36.8% (95%CI 20.6-53.2), HR: 0.39 (95%CI 0.005-0.29) p=0.002 (Figure 2). Conclusion MRD assessment is a strong prognostic in ALL, however it was not associated with significant differences in RFS or OS in this single institution cohort of Colombian patients. Patients with PMRD taken to AlloHSCT had superior OS compared to NMRD that underwent transplant. A small sample size and short follow-up could explain our results. Larger cohorts with extended follow up and with different MRD methods are needed to better understand the role of MRD assessment in minority ALL populations, such as Colombian patients. Figure 1 Figure 1. Disclosures Peña: Amgen: Research Funding. Salazar: Amgen: Research Funding. Sandoval-Sus: BMS: Other: Advisory Board, Speakers Bureau; SeaGen, Janssen, MassiveBio, TG: Other: Advisory Board. Sossa: Amgen: Research Funding.

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Baseline Hypoalbuminemia Does Not Appear to be an Adverse Prognostic Factor in Patients with Relapse/Refractory B-Cell Lymphomas Treated with Axicabtagene Ciloleucel (axi-cel)

Blood ◽

10.1182/blood-2019-126594 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5343-5343

Author(s):

Megan Melody ◽

Sangeetha Gandhi ◽

Zaid Abdel Rahman ◽

Paula A Lengerke Diaz ◽

Nicole Gannon ◽

...

Keyword(s):

Serum Albumin ◽

B Cell ◽

Mayo Clinic ◽

Research Funding ◽

Response Rate ◽

Normal Serum ◽

Advisory Board ◽

Genetics Research ◽

Significant Difference

BACKGROUND: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that is approved for treatment of relapsed/refractory (R/R) large B-cell lymphoma and is associated with high response rates and durable remissions. Recent data show that axi-cel is effective across various adverse prognostic features, namely cell of origin, disease bulkiness, and extranodal disease, among others. Hypoalbuminemia is a known adverse prognostic factor in lymphomas. It is unknown if axi-cel overcomes the adverse prognostic feature of hypoalbuminemia in R/R large B-cell or transformed follicular lymphoma. METHODS: We conducted a retrospective analysis of patients treated with axi-cel across three Mayo Clinic campuses (Rochester, Jacksonville, and Phoenix) from 06/01/2018 until 04/01/2019. The primary objective of this analysis was to assess the impact of hypoalbuminemia (defined at day 0, prior to infusion) on outcome after axi-cel therapy. RESULTS: A total of 50 (male=37, 74%) patients (pts), median age of 53 (26-67) years received axi-cel. The median number of prior lines of therapy was 3 (2-8) (Table 1). Two pts had no available serum albumin levels at time of axi-cel infusion. Seven (15%) of 48 pts had serum albumin levels lower than 3.5 g/dL (median= 3.3 g/dL (range 2.6-3.4)) and the median follow up of survivors was 7.6 (1.9-14.3) months. The best overall response rate (ORR) and complete remission (CR) rates in these pts were 57% and 57%, respectively. One (14%) patient had stable disease and 2 (29%) had disease progression. The median overall survival (OS) for pts with hypoalbuminemia was not reached. On the other hand, 41 (85%) pts had a normal serum albumin level (median=4.0 (range 3.5-5.1) g/dL) and the median follow up for survivors was 6.3 months. The best objective response rate (ORR) and complete remission (CR) rates in these pts were 82% and 44%, respectively. The median OS for pts with normal serum albumin was 14 (95%CI=6.3-29.6) months. There was no significant difference at 6-months and 1-year OS between pts with hypoalbuminemia vs. those with normal baseline serum albumin levels [6-month=100% vs. 79%(95%CI=64-93%); 1-year (100% vs. 54% (95%CI=26-82%), p=0.17] (Figure 1). All grades cytokine release syndrome (CRS) was diagnosed in all 7 pts with hypoalbuminemia (100%) and in 38 of 41 (92%) pts without hypoalbuminemia. There was no difference in the median duration of CRS between pts with or without hypoalbuminemia [6 (range 1-11) days vs 5 (range 1-19) days, p=0.89]. Neurotoxicity (all grades) was observed in 5 (71%) pts with hypoalbuminemia compared 26 (63%) with normal albumin levels. There was no statistically significant difference in median duration of neurotoxicity between pts with hypoalbuminemia and those with normal baseline albumin levels [9 (range 1-10) days vs. 3 (range 0-25) days, p= 0.72]. CONCLUSIONS: Hypoalbuminemia does not have a significant impact on the outcomes of axi-cel therapy, including the incidence of CRS or neurotoxicity. These results need to be validated in a large collaborative multicenter study. Further investigation is needed to assess the prognostic impact of severe hypoalbuminemia (<3g/dL) on axi-cel therapy. Disclosures Ansell: Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Affimed: Research Funding. Bennani:Seattle Genetics: Other: Advisory board; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board. Paludo:Verily Life Sciences: Research Funding; Celgene: Research Funding; Verily Life Sciences: Research Funding; Celgene: Research Funding. Tun:DTRM Biopharma: Research Funding; Mundi-pharma: Research Funding; BMS: Research Funding; Celgene: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding. Foran:Agios: Honoraria, Research Funding. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy.

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Inotuzumab Ozogamicin Is an Effective Salvage Therapy in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia with High-Risk Molecular Features, Including TP53 Loss

Blood ◽

10.1182/blood-2019-125165 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3888-3888 ◽

Cited By ~ 1

Author(s):

Xiaochuan Yang ◽

Amber C. King ◽

Charlene C. Kabel ◽

Christopher J. Forlenza ◽

Jae H. Park ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

High Risk ◽

B Cell ◽

Response Rate ◽

Lymphoblastic Leukemia ◽

Advisory Board ◽

Inotuzumab Ozogamicin ◽

Ras Mutations ◽

Molecular Features ◽

Cell Acute Lymphoblastic Leukemia

Introduction: Adults with (w/) B-cell acute lymphoblastic leukemia (B-ALL) exhibit high rates of complete response (CR) to induction chemotherapy, but relapse is common. Inotuzumab ozogamicin (IO), an antibody-drug conjugate targeting CD22, achieves high rates of CR in patients (pts) w/ relapsed/refractory (R/R) B-ALL and is FDA-approved for R/R B-ALL in adults. It remains unknown whether cytogenetic and molecular features associated w/ decreased response rate and poor prognosis following conventional chemotherapy are associated w/ response to IO. As such, we investigated the relationship between several high-risk genetic alterations and outcome following IO treatment in pts w/ R/R B-ALL. Methods: We reviewed electronic medical records of pts of all ages w/ R/R B-ALL or chronic myeloid leukemia in lymphoid blast phase (CML-LBP) receiving IO at Memorial Sloan Kettering Cancer Center (MSK) between January 2011 and April 2019. The primary objective was to assess whether recurrent cytogenetic or molecular features were associated w/ achievement of CR or CR w/ incomplete hematologic recovery (CRi), w/ or w/o measurable residual disease (MRD), and disease-free (DFS) and overall survival (OS) following IO. Secondary objectives included association of baseline clinical features, including central nervous system (CNS) or other extramedullary (EM) disease, w/ outcomes post-IO. MRD was defined as any unequivocal evidence of B-ALL detectable by RT-PCR (Ph+ ALL) or flow cytometry (FACS). Genomic alterations were defined by MSK IMPACT-Heme (Cheng, J Mol Diagn, 2015), FoundationOne Heme, or similar platforms. A set of selected high-risk (HR) features in Philadelphia chromosome-negative (Ph-) B-ALL was defined prior to the analysis (HR: mutations/loss of TP53, IKZF1/3, CDKN2A, CREBBP; activating RAS mutations; "Ph-like" profile). DFS and OS were computed using Kaplan-Meier methods and compared between groups using log-tank tests. Results: 32 pts (13F, 19M) w/ R/R B-ALL (n=31) or CML-LBP (n=1) treated w/ IO were identified. IO was given as monotherapy in 27 pts and w/ other systemic therapy in 5 pts (mini-hyper-CVD-like regimen, n=4; ponatinib, n=1). Median age at start of IO was 45 years (range 3-78). 10 pts had undergone prior allogeneic hematopoietic cell transplantation (alloHCT). Seven and 15 pts had a history of CNS disease or other EM involvement by B-ALL, respectively, including 3 and 6 pts immediately prior to IO, respectively. Pts received a median 3 lines of salvage prior to IO, including prior CD19-targeted immunotherapy (blinatumomab and/or CAR-T cells) in 24 pts(Table 1). Among 27 pts w/ Ph- B-ALL, 12 had the selected HR features (Table 2). Five pts had Ph+ ALL (n=4) or CML-LBP (n=1) and 5/5 harbored ABL1 kinase domain point mutations (4/5 w/ T315I mutation). 22 pts had at least one successful molecular profiling panel.29 patients had initial cytogenetic studies, of whom 28 patients had evaluable karyotypes. 23 pts had best response to IO of CR/CRi (MRD-, n=15; MRD+, n=8). 9 pts had no objective response to ≥1 cycle of IO. Of the 12 Ph- pts w/ selected HR mutations, 11 achieved CR/CRi. Notably, 6/6 pts w/ TP53 mutation/deletion and 5/5 pts w/ IKZF1/3 mutations (3/3 pts w/ both TP53 & IKZF mutations) achieved CR/CRi. Both pts w/ Ras mutations and 2/3 w/ Ph-like B-ALL achieved CR/CRi. 7/11 HR responders underwent alloHCT post-IO (3 had undergone pre-IO alloHCT). Pts w/ Ph- B-ALL w/ HR mutations demonstrated similar CR/CRi rate and OS to pts w/ Ph- B-ALL w/o defined HR mutations (Fig 1A-B). In contrast, only 1/5 pts w/ Ph+ ALL achieved CR/CRi (was MRD+) and 4/5 showed persistent B-ALL. OS was superior among pts w/ Ph- vs Ph+ B-ALL post-IO (8.0 vs 1.9 months, p=0.0068, Fig 1C). Among pts w/ EM disease immediately prior to IO, 3/6 achieved CR/CRi, including CR in 1 pt w/ a cardiac mass. Median DFS was 3.2 months vs. not reached following achievement of MRD+ vs MRD- CR, respectively (p=ns, Fig 1D). Conclusions: HR molecular features associated w/ poor response to chemotherapy were not associated w/ inferior response rate and overall prognosis following IO in this small series. Notably, pts w/ Ph+ ALL (all w/ ABL1 mutations) exhibited suboptimal response, possibly as pts received IO only in advanced disease states following TKI failure. This small report supports investigation of IO in frontline therapy for pts w/ B-ALL w/ HR mutations to spare unnecessary toxicities of chemotherapy and bridge successfully to alloHCT. Disclosures King: Genentech: Other: Advisory Board ; Astrazeneca: Other: Advisory board; Incyte: Other: Advisory Board. Park:Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Geyer:Dava Oncology: Honoraria; Amgen: Research Funding. OffLabel Disclosure: Inotuzumab ozogamicin is not FDA approved for pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia.

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Outcome by Treatment Including An Intensified Consolidation Program with Dose-Escalated Doxorubicin for Newly Diagnosed Acute Lymphoblastic Leukemia (ALL): A Study by the Japan Adult Leukemia Study Group (JALSG ALL97 study).

Blood ◽

10.1182/blood.v114.22.4334.4334 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4334-4334

Author(s):

Itsuro Jinnai ◽

Tohru Sakura ◽

Motohiro Tsuzuki ◽

Yasuhiro Maeda ◽

Noriko Usui ◽

...

Keyword(s):

Prognostic Factors ◽

Acute Lymphoblastic Leukemia ◽

High Risk ◽

Risk Group ◽

Lymphoblastic Leukemia ◽

Long Term Outcome ◽

Allogeneic Hsct ◽

Wbc Count ◽

Standard Risk ◽

Group 1

Abstract Abstract 4334 BACKGROUD We designed a multicenter study (JALSG ALL 97) including an intensified consolidation program with dose-escalated doxorubicin (DOX) in order to improve outcome in adults with acute lymphoblastic leukemia (ALL) in pre-imatinib era. We reported here the efficacy and prognostic factors of mainly Philadelphia chromosome (Ph)-negative patients. METHODS From May 1997 to December 2001, patients (age ranges 15 - 64 years) with previously untreated ALL (excluding mature B-cell ALL) were consecutively registered in this study. We modified the standard induction program with five drugs; vincristine (VCR), daunorubicin, cyclophosphamide, prednisolone (PSL) and L-asparaginase and the maintenance program with daily 6-mercaptopurine, weekly methotrexate (MTX) and monthly pulses of VCR and PSL used in CALGB 8811 study. Consolidation therapy included eight courses featuring dose-intensified DOX and intermediate-dose MTX. The total dose of DOX in consolidation phase was 330 mg/m2. For patients with Ph or t(4;11), allogeneic stem cell transplantation (HSCT) was recommended during their first complete remission (CR), if donors were available; whereas for patients without Ph or t(4;11) there was no criteria for choosing HSCT. The 5-year overall survival (OS), the 5-year disease-free survival (DFS), and the prognostic factors were evaluated. RESULTS There were 404 eligible patients (median age, 38 years), of whom 256 were Ph-negative and 116 were Ph-positive. Of the eligible patients, 298 patients (74%) achieved CR. With a median follow-up time of 5.8 years, the estimated 5-year OS rate was 32% (95%CI: 27.1-36.9), and the 5-year DFS was 33% (95%CI: 26.8 - 38.2). The CR rates in Ph-negative and Ph-positive patients were 81% (n=208) and 56% (n=65), respectively. The 5-year OS in Ph-negative and Ph-positive patients were 39% and 15%, respectively. In Ph-negative patients, multivariate Cox analysis showed that older age, PS and WBC count were the independent prognostic factors for OS. The 5-year OS rates for patients younger than 35 years and a WBC count less than 30 × 109/L (risk group 1), for patients younger than 35 years and a WBC count above 30 × 109/L (risk group 2), for patients older than 35 years and a WBC count less than 30 × 109/L (risk group 3), and for patients older than 35 years and a WBC count above 30 × 109/L (risk group 4), were 51%, 29%, 33%, and 27%, respectively (P=0.0005). Of the 208 Ph-negative patients who achieved CR, 60 patients (29%) were underwent allogeneic-HSCT during their first CR (37 from a related donor and 23 from an unrelated donor), resulting that 8 (13%) died in remission, 16 (27%) relapsed, and 36 (60%) remained in continuous CR. The 5-year OS rate for the 60 patients was 63 %. Among them, the 5-year OS rates for the 31 patients of the risk group 1 (standard risk group) and for other 29 patients (high risk group) were 73% and 54%, respectively. Among 148 patients who did not receive allogeneic-HSCT during first CR, six (4 %) died in remission, 105 (71%) relapsed, and 37 (25%) remained in continuous CR. The 5-year OS rates for the 148 patients, for patients with standard risk, and for patients with high risk were 37%, 44% and 33%, respectively. CONCLUSION Result of this study was in the range of those reported by most large cooperative groups, but showed little improvement of adult Ph-negative ALL therapy. The prognostic factors for long term outcome of Ph-negative patients were similar to those in previous reported. This study also suggested that allogeneic-HSCT for Ph-negative patients in first CR might have contributed to the improvement of the outcome. Disclosures: No relevant conflicts of interest to declare.

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Mutation Analysis of JAK-1, 2 and 3 in Children with Down Syndrome and Acute Leukemia.

Blood ◽

10.1182/blood.v114.22.5035.5035 ◽

2009 ◽

Vol 114 (22) ◽

pp. 5035-5035

Author(s):

Marjolein Blink ◽

Trudy Buitenkamp ◽

Astrid A Danen-van Oorschot ◽

Valerie de Haas ◽

Dirk Reinhardt ◽

...

Keyword(s):

Down Syndrome ◽

Acute Lymphoblastic Leukemia ◽

High Risk ◽

Lymphoblastic Leukemia ◽

Janus Kinase ◽

Children With Down Syndrome ◽

Activating Mutations ◽

Increased Risk ◽

Frequent Event

Abstract Abstract 5035 Children with Down Syndrome (DS) have an increased risk of developing leukemia, including both acute myeloid (ML-DS), as well as acute lymphoblastic leukemia (DS-ALL). ML-DS can be preceded by a pre-leukemic clone in newborns (transient leukemia-TL), which in most cases resolves spontaneously. Janus Kinase (JAK) 1-3 belongs to a family of intracellular non-receptor protein tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. JAK plays an important role in regulating the processes of cell proliferation, differentiation and apoptosis in response to cytokines and growth factors. Mullighan et al. described JAK 1-3 mutations in non-DS high-risk childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL; PNAS, 2009). In T-ALL, JAK-1 mutations are a frequent event (∼25%) as reported among others by Jeong et al (Clinical Cancer Research, 2008). Mutations in JAK-2 and JAK-3 have been described in TL and ML-DS. Bercovich et al. recently reported mutations within the pseudokinase domain of JAK-2 in DS-ALL patients (Lancet 2008). This activating JAK-2 mutation differs from the V617F exon 14 mutation found in myeloproliferative diseases. However, JAK-1 has never been investigated in Down syndrome leukemias. Therefore we performed mutational analysis of the pseudokinase and kinase domains of JAK-1, 2 and 3 by direct sequencing in 8 TL, 16 ML-DS and 35 DS-ALL samples taken at initial diagnosis. The TL and ML-DS samples were unpaired. In the ML-DS group, 12 patients were classified as FAB M7, 3 as FAB M0 and 1 as FAB M6; all 35 DS-ALL patients were classified as BCP-ALL. Mutations in JAK-1 were found in 1 ML-DS patient (D625R) and in 1 DS-ALL patient (V651M). These mutations were localised in the same region of the pseudokinase domain, but not identical to the activating mutations in JAK1 described in high-risk ALL (Mullighan et al., PNAS 2009). The JAK-1 mutated ML-DS patient had a complex karyogram, and the DS ALL patient a normal karyotype. No events occurred in either of the patients with a follow-up of 2.4 and 3.1 years, respectively. JAK-2 activating mutations at position R683 were found in 5/35 (14.3%) of the DS-ALL patients. These patients had diverse cytogenetic aberrations, and had no events at a median follow up of 4.4 years. In the TL and ML-DS patients no mutations were identified in JAK-2. For JAK-3, 1 TL-patient (13%) and 1 ML-DS patient (6.3%) harboured the A573V-mutation. This activating mutation is previously described in ML-DS patients and the megakaroyblastic cell line CMY ((Kiyoi et al, Leukemia 2007). Because the mutations occur in both TL and ML-DS, this suggests that they do not play a role in the clonal progression model from TL to ML-DS. A mutation at JAK3 R1092C, which to our knowledge has never been reported before, was found in 1 DS-ALL patient. This patient had a deletion on chromosome 12 (p11p13), and was in CCR with a follow up of 5 years. In conclusion, JAK-mutations are rare in DS-leukemias, except for JAK-2 mutations in DS-ALL, which occur in approximately 15% of cases. The rarity of JAK-1 mutations in DS is in accordance with the rarity of T-ALL in DS. Of interest, none of the DS ALL cases with a JAK-2 mutation relapsed so far, which differs from the patients with JAK-2 mutations that were recently in high-risk BCP-ALL. Hence, JAK-2 may be an interesting novel therapeutic target. Disclosures No relevant conflicts of interest to declare.

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Pediatric Therapy In Adult Acute Lymphoblastic Leukemia: Updated Experience of a Single Centre

Blood ◽

10.1182/blood.v116.21.4338.4338 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4338-4338

Author(s):

Stefania Paolini ◽

Sarah Parisi ◽

Ilaria Iacobucci ◽

Cristina Papayannidis ◽

Maria Chiara Abbenante ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Hematological Toxicity ◽

Induction Phase ◽

Single Centre ◽

Phase Ib ◽

Small Series ◽

Significant Difference

Abstract Abstract 4338 Background. Acute lymphoblastic leukemia (ALL) presents with different outcome in children and adults, with event-free-survival (EFS) rates of 70–80% and 30–40% at 5 years, respectively. This reflects both a different disease biology and different therapeutic approaches. Recently, results apparently improved in young adults/adolescents aged 15–21 years, with de novo ALL, when treated with pediatric intensive regimens rather than with typical adult regimens. Similarly, clinical studies are ongoing in older patients, toxicity related-therapy seeming the limiting issue. Aims. We report a single centre experience on adult ALL patients treated with an intensive pediatric-inspired schedule, designed to assess its tolerability and efficacy. Methods. From November 2007 to June 2010 seventeen ALL patients (M/F=12/5) were treated at our Center according to a modified AIEOP LAL2000 regimen. Treatment consisted of 7 days steroid pre-treatment, and four drugs 78-days induction (phase IA and phase IB) after which high risk (HR) patients were treated with three polychemotherapy blocks, while intermediate (IR) and standard risk (SR) patients went on 8-weeks consolidation and subsequent delayed intensification. Allo-SCT was planned for all patients with HLA-matched donor, as alternative to 2-years maintenance therapy. Median age was 31 years (range, 17–47). According to cytogenetic, response to steroid and minimal residual disease patients were classified into HR (n=7), IR (n=6) and SR (n=4). Results. 15/17 patients completed the induction phase IA, two being out for toxicity (grade IV infection and intestinal occlusion). Twelve (71%) obtained a complete remission (CR); three were refractory. However, one of them subsequently achieved CR after polychemotherapy blocks, for an overall response rate of 76% (13/17). Eleven patients then completed the 28-days induction IB. One patient is ongoing. Median induction duration was 92 days (range 82–136). Delays were mostly due to extra-hematological toxicity, the commonest being gastrointestinal (n=12), infective (n=7) and thrombotic (n=3). Delays were accumulated in both induction phases without significant difference between phase IA (median 18.5 days, range 4–37) and phase IB (median 17 days, range 9–66), despite an absolute number of moderate-severe AE superior in phase-IA versus phase-IB (12 vs 5). After induction, 4/12 patients already received consolidation therapy; 2/4 then received allo-SCT. The median duration of consolidation was 51 days (range 22–94). Conversely, 6/12 patients received polychemotherapy-blocks, one patient went directly on alloSCT and the remaining is ongoing. After polychemotherapy-blocks, five out six patients received allo-SCT. The median CR duration was 13 months (range 1+-42+); two patients relapsed, both after allo-SCT. With a median follow-up of 11 months (range 2–43) 11/17 (65%) patients are alive, 9 in CR (5 undergone allo-SCT). Six patients dead, three in CR for infectious complications, 3 for relapsed/refractory disease. Conclusions. Though in a small series, pediatric-like intensive chemotherapy seemed to be feasible in adult ALL. Extra-hematological toxicity, however, caused significant treatment delays during induction. Finally, the overall outcome appeared promising, though longer follow-up and larger populations are needed to draw definitive conclusions. Acknowledgments. BolognAIL, European LeukemiaNet, AIRC, Fondazione Del Monte di Bologna e Ravenna, FIRB 2006, PRIN 2008, Ateneo RFO, Project of Integrated Program (PIO), Programma di Ricerca Regione – Università 2007–2009. Disclosures: No relevant conflicts of interest to declare.

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Alemtuzumab Plus Oral Dexamethasone, Followed by Alemtuzumab Maintenance or Allogeneic Transplantation in Ultra High-Risk CLL: Interim Analysis of a Phase II Study of the GCLLSG and fcgcll/MW

Blood ◽

10.1182/blood.v118.21.2854.2854 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2854-2854 ◽

Cited By ~ 2

Author(s):

Stephan Stilgenbauer ◽

Florence Cymbalista ◽

Véronique Leblond ◽

Alain Delmer ◽

Dirk Winkler ◽

...

Keyword(s):

High Risk ◽

Research Funding ◽

Response Rates ◽

Long Term Results ◽

High Dose ◽

Significant Difference ◽

Ultra High Risk ◽

Grade 3 ◽

The Impact

Abstract Abstract 2854 Alemtuzumab (A) proved to be efficacious in CLL patients (pts) with very poor prognosis, either due to fludarabine (F) refractoriness or due to unfavorable cytogenetics (17p-). However, rate and duration of remissions still remain unsatisfactory. Therefore, the French and German CLL study groups jointly embarked on this trial, trying to achieve higher overall response rates (ORR) by adding high-dose dexamethasone (D) to A and, simultaneously, investigating the consolidation effect of prolonged A maintenance or allogeneic stem-cell transplantation (allo-SCT), respectively. Induction treatment consisted of subcutaneous A 30 mg weekly × 3 for 28 days, combined with oral D 40 mg on days 1–4 and 15–18, and prophylactic pegfilgrastim 6 mg on days 1 and 15. Depending on the remission status, pts were treated for up to 12 weeks. If CR was documented at 4 or 8 weeks, or at least SD was achieved at 12 weeks, consolidation was scheduled with either allo-SCT or A maintenance with 30 mg every 14 days for up to 2 years (y), at the discretion of pt and physician. Between January 2008 and July 2011, 124 pts were recruited at 26 centers, 120 of whom were eligible. Pts were generally subdivided into three cohorts: 55 pts were refractory (i.e. no response or relapse within 6 months) to regimens containing F or a similar drug (i.e. pentostatin, cladribine, bendamustine). Non-refractory pts all exhibited 17p- and had either untreated (n=39) or relapsed CLL (n = 26) requiring therapy. The median age was high with 66/64/66 y in 17p- 1st line, 17p- relapse, and F-refractory pts, respectively. The three cohorts had 46/54/75% Binet C disease, 41/35/27% B symptoms, 38/42/53% reduced performance status (ECOG 1/2), median thymidine kinase levels of 35/49/24 U/L, median ß2MG levels of 3.8/5.5/4.6 mg/L, and IGHV was unmutated in 89/96/87%. In the F-refractory group, 53% exhibited 17p deletion and 22% had 11q deletion. Pretreated patients had received a median of 3 (F-refractory) or 2 prior lines (17p- relapse). 5 pts had previously undergone autologous and 1 pt allo-SCT. Treatment and efficacy data are currently available for 87 pts who completed induction therapy :17p- 1st-line (n=30), 17p- relapse (n=17), and F-refractory (n=40). Of these, 80/53/55% received the full induction of 12 weeks. ORR (best observed status) was generally high with 97/76/70%. CR was achieved in 20/0/5%. After a median follow-up of 11.8 months (mo), median progression-free survival (PFS) was 16.9/10.4/8.4 mo. Deaths are recorded in 13/27/36% of pts, with median overall survival (OS) not yet reached (>24 mo) in the 17p- 1st line group, and 15/12 mo in 17p- relapse/F-refractory pts. Consolidation treatment was performed as maintenance A (median duration 32 weeks, range 2 – 89) in 34%, and allo-SCT in 30%, with a median age of 66 and 61 y in these subgroups. The main reasons for going off-study without consolidation were death due to infection (14%, n=11, of these 6 without response, and 10 in the F-refractory cohort), CLL progression (12%), and other toxicity (5%). Among the 28 pts not receiving consolidation, there were 19 (68%) deaths, 15 of them in the F-refractory cohort. When comparing A maintenance and allo-SCT for consolidation, there were 9 (35%) and 7 (30%) PD events, respectively and there was so far no significant difference in PFS (median 17 mo in both groups) or OS. During induction, grade 3/4 hematotoxicity consisted of anemia in 28%, neutropenia in 47%, and thrombopenia in 44%. Grade 3/4 non-CMV infection occurred in 29% of 17p- 1st-line, 15% of 17p- relapsed, and 56% of F-refractory pts. CMV reactivation was observed in 54/25/40%, without severe sequelae recorded. During A maintenance, grade 3/4 toxicity consisted of neutropenia in 39% pts and thrombopenia in 4% pts with 6 SAEs (ITP, diarrhea, infection, erythema, tachycardia, and thrombosis). Conclusions: The combination of A and D shows high response rates in ultra high-risk CLL, with promising preliminary findings for PFS and OS, despite the high median age of the pts. The results compare favorably to ORR/CR of 68%/5%, and median PFS of 11.3 mo in the 17p- subgroup of the CLL8 study treated with FCR, consisting of younger pts (median 61 y). In F-refractory CLL however, when compared to the preceding CLL2H study with single agent A, the improved initial response by adding dexamethasone does not seem to translate into improved long-term results. More mature follow-up is needed, especially with respect to the impact of allo-SCT. Disclosures: Stilgenbauer: Amgen: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding. Off Label Use: Alemtuzumab in 1st line CLL treatment. Cymbalista:Roche (d) Mundipharma (e) Genzyme (e): Honoraria, Research Funding. Hinke:WiSP (CRO): Employment.

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