Therapy-related Acute Lymphoblastic Leukemia Research Articles

Mutational patterns in therapy-related acute lymphoblastic leukemia subgroups: one step closer to unveiling the genetic odyssey

There is increasing evidence that therapy-related acute lymphoblastic leukemia (trALL) resulting from chemo- and/or radiotherapy represents a distinct entity. However, apart from KMT2A rearrangements, which have been repeatedly reported in this subgroup, the relevance of other aberrations remains controversial due to divergent study results and sparse molecular analyses. Within our ALL patient cohort, 15% (n = 19/131) met the criteria for trALL with a high proportion of Ph + and KMT2A rearrangements. On the molecular level, the most frequently observed mutation was KMT2D, followed by CDKN2A, KRAS and DNMT3A. No TP53 mutation was detected. Outcome was particularly poor in Ph + trALL compared to Ph+ de novo ALL, which seemed to be mitigated by allogeneic stem cell transplantation. Our findings further define trALL as a distinct entity but highlight the need for further molecular genome sequencing of somatic and germline variants to advance our understanding of trALL.

Chemotherapy-free treatment with inotuzumab ozogamicin and blinatumomab for older adults with newly diagnosed, Ph-negative, CD22-positive, B-cell acute lymphoblastic leukemia: Alliance A041703.

7006 Background: Older adult patients (pts) with Philadelphia-chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) have poor survival with chemotherapy. The α-CD22 Ab-drug conjugate inotuzumab ozogamicin (InO) and α-CD19/CD3 T-cell engager blinatumomab (blina) were each superior to chemotherapy in Phase III studies in relapsed/refractory B-ALL. Because InO induces high CR rates and blina can induce durable remissions in low burden disease, we conducted a Phase II trial of induction InO then blina for older adults with newly-diagnosed (ND), Ph-, B-ALL. Methods: Eligible were pts ≥60 years old with ND, Ph-, CD22+ (≥20% of blasts) B-ALL without plan for allogeneic HCT (alloHCT). Pts with CNS leukemia or liver disease were excluded. Induction IA was InO 0.8 mg/m2 day (d) 1, 0.5 mg/m2 d8, d15 IV on a 21d cycle. Pts with adequate cytoreduction (marrow blasts by ≥50% or cellularity ≤20%) after IA went to IB if in CR/CRi (InO 0.5 mg/m2 d1, d8, d15 IV; 28d cycle) or IC if no CR/CRi (InO 0.8 mg/m2 d1, d8, d15 IV; 28d cycle). Those without cytoreduction to IA started course II blina. Pts without events in IA/B/C received course II blina CIV (9 mcg/d x 7d then 28 mcg/d x 21d; 14d break; 28 mcg/d x28d). Pts with CR/CRi to InO received 2 more 28d cycles of blina, others received 3 more. CNS prophylaxis was methotrexate 15 mg intrathecal x 8. The primary endpoint was 1-yr event-free survival (EFS) with a lower limit of a 90% CI for 1-yr EFS >10% defined as success. EFS was the time from therapy start to failure to achieve CR/CRh/CRi by end Course II, progression, relapse, or death, whichever occurred first. Results: Thirty-three eligible pts were treated (1 ineligible, 2nd malignancy). The median age was 71 years (range 60-84). Median WBC count was 3,200/mcl (range 6-38,000). Median CD22 expression was 92% (range 21-100%). Eight pts had therapy-related ALL. The cumulative CR rates through Course IA/B/C and Course II were 85% and 97%, respectively (Table). With median follow up of 22 mo, the 1-yr EFS was 75% (95% CI 61-92%). The 2-sided 90% CI was 63-89% for 1-yr EFS with lower bound above 10% indicating regimen success. Twelve pts had events: 9 relapses, 2 deaths in remission (1 after alloHCT), and 1 death without remission from respiratory failure with sinusoidal occlusion syndrome of liver. The 1-yr OS was 84% (95% CI 72-98%). Nine pts have died, 6 after relapse. Conclusions: InO induction then blina consolidation is highly active for ND, Ph-, CD22+ B-ALL. The regimen is an option for older adults and a comparator regimen for future studies. Support: U10CA180821, U10CA180882, U10CA180820 https://acknowledgments.alliancefound.org . Clinical trial information: NCT03739814 . [Table: see text]

Molecular Characterization of Adult Acute Lymphoblastic Leukemia Identifies a Subgroup with Myeloid Mutations and Pre-Existing Clonal Hematopoiesis

Acute lymphoblastic leukemia (ALL) represents 20% of adult leukemias. Genomic risk stratification of ALL relies on the data generated from large cohorts of pediatric and young adult patients, where older patients with ALL have been underrepresented. It is imperative to understand the unique leukemogenic pathways in this group in order to develop novel therapeutic approaches. Clonal hematopoiesis (CH) is a precursor lesion for development of myeloid leukemias and mature lymphoid neoplasms (Niroula, Nat Med 2021), but its impact on the biology and outcomes of ALL is unknown. Based on our observations on high incidence of myeloid mutations in older adults with ALL, we hypothesized that CH constitutes a fertile genomic background for lymphoblastic leukemogenesis, and ALL with myeloid mutations is a unique entity with distinct clinical and molecular characteristics. We studied 400 adult patients with ALL treated at the University of Chicago, Moffitt Cancer Center, and City of Hope between 2014 and 2022 (Fig 1A). Genetic profiling of pre-treatment bone marrow samples was performed with a comprehensive panel covering 147 myeloid and lymphoid genes. Overall, 33% of ALL cases had at least one myeloid CH-associated mutation with the following frequencies: TP53 (18%), DNMT3A (5%), TET2 (4%), ASXL1 (3%), RUNX1 (3%), IDH2 (2%), BCORL1 (2%), U2AF1 (1%), CUX1 (1%), BCOR (1%), CBL (1%), and SF3B1 (1%). We further investigated the association between mutations and clinical variables by calculating the odds-ratios (OR) with adjustments for multiple testing by using the Benjamini-Hochberg method. Myeloid CH mutations in TP53, DNMT3A, TET2, and ASXL1 genes were more common in older adults with ALL. Mutations in TP53 and DNMT3A were enriched in therapy-related B-ALL group (OR 2.6, 95% CI= 1.3-5.5, q= .007 and OR 4.7, CI= 1.2-18.1, q= .01, respectively), and were more commonly associated with hypodiploid (OR 7.1, 95% CI= 1.5-32.7, q=.004 and OR 5.2, 95% CI= 0.6-48, q=.1, respectively) and hyperdiploid (OR 5.9, 95% CI= 2.7-13.1, q=<0.001 and OR 3.9, 95% CI= 1.1-16.5, q=.04, respectively) cytogenetics. We stratified the ALL cohort into three groups: TP53-mutated ALL, non-TP53 CH-associated ALL, and ALL without myeloid CH mutations. Patients in both groups of CH-associated B-ALL had worse overall survival (OS) than patients without myeloid CH mutations (median OS, 23 vs 25 vs 48 months, respectively, p=.001). In a multivariable analysis of OS for B-ALL, adjusting for age and therapy-related ALL, both TP53 (HR 1.95, 95% CI=1.2-3.17, p=.006) and non-TP53 myeloid CH (HR 1.95, 95% CI=1.14-3.35, p=.01) were associated with worse OS. Based on the data indicating high allelic frequencies of myeloid CH mutations in ALL, we hypothesized that these mutations are ancestral events arising in HSCs. To gain insights into the clonal architecture, we performed single cell DNA+protein sequencing using the Mission Bio, lnc platform. Data from 4,180 cells obtained from a CH-associated B-ALL patient are shown in Fig 1B. Cells were clustered by immunophenotype, and mutations were overlayed into 8 clusters. IDH2 R140Q mutation was shared between ALL and myeloid compartments. PTPN11 mutation was more prevalent in B-lymphoblasts. We observed a similar pattern in 7 additional patients, indicating that both lymphoblasts and non-malignant myeloid cells share CH mutations in ALL patients. Next, we investigated whether CH can be detected as a precursor lesion prior to ALL. In a patient with therapy-related B-ALL, a TET2 CH clone was detectable 5 years prior to ALL, and additional SF3B1 and CDKN2A mutations were detectable at the time of B-ALL diagnosis. We confirmed the presence of these mutations in B-lymphoblasts by single cell sequencing. This patient had persistent TET2/SF3B1 mutated CH despite achieving remission from B-ALL. We observed a similar pattern in four additional patients, for whom the CH mutations were detectable several years prior to their ALL diagnosis and were present in the dominant ALL clone. Collectively, these data support a model in which ALL can arise from pre-existing clones harboring myeloid CH mutations in a significant fraction of older adults. ALL with myeloid mutations is a distinct clinicopathologic entity with inferior survival outcomes. Future studies may decipher mechanisms driving lymphoid bias of CH-mediated leukemogenesis that can be targeted to prevent and treat ALL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical and Biological Characteristics and Outcomes of Therapy-Related Acute Lymphoblastic Leukemia (t-ALL) Following Multiple Myeloma Are Distinct in Comparison to t-ALL Following Other Cancers

Clinical and Biological Characteristics and Outcomes of Therapy-Related Acute Lymphoblastic Leukemia (t-ALL) Following Multiple Myeloma Are Distinct in Comparison to t-ALL Following Other Cancers

Unique Characteristics and Outcomes of Therapy-Related Acute Lymphoblastic Leukemia (trALL) Following Therapy for Multiple Myeloma (MM)

Unique Characteristics and Outcomes of Therapy-Related Acute Lymphoblastic Leukemia (trALL) Following Therapy for Multiple Myeloma (MM)

Therapy-Related ALL Has Distinct Clinical and Pathologic Features Compared to De Novo ALL

Therapy-related acute lymphoblastic leukemia (t-ALL) is an emerging entity that encompasses cases of ALL that develop after prior exposure to cytotoxic therapy. We retrospectively reviewed all consecutive cases of adult ALL treated at City of Hope between 2000 and 2017 in order to identify cases of t-ALL. We defined t-ALL defined as ALL that occurred after prior exposure to chemotherapy and/or radiation and/or immunomodulatory agents. We excluded cases of ALL preceded by malignancy but without exposure to cytotoxic therapy. We compared t-ALL cases with de novo ALL cases treated during the same period to identify distinctive features.We identified 92 cases of t-ALL among 995 cases treated representing 9% of all adult ALL. The median age for t-ALL patients was 55 (23-85) yrs old, and the median latency for developing ALL was 6.6 (0.8-50.7) yrs from the time of original malignancy/disease diagnosis. Prior diagnosis was solid cancer in 50 (54%), hematological cancer in 34 (37%), combination of solid/blood caner in 2 (2%), and benign disease in 6 (7%) patients. Breast cancer was the most common prior diagnosis (N = 21), and this was followed by non-Hodgkin's lymphoma and multiple myeloma (13 cases each). 34 (37%) patients had prior chemotherapy only, 25 (27%) had prior radiotherapy only, 31 (34%) had prior combination of chemo-radiation, 17 (18%) received prior autologous transplant, and 15 (16%) had immunomodulatory agents. 2 cases of t-ALL were preceded by MDS. Phenotype was precursor B-cell in 84 (91%) patients. The latency interval from original diagnosis to ALL onset was shorter in patients carrying MLL gene rearrangement compared to patients carrying Philadelphia chromosome (Ph+) or other cytogenetic subgroups (2.4 yrs vs. 6.6 yrs vs. 7.3 yrs, p < 0.01), respectively, but there was no difference in latency based on type of cytotoxic therapy or prior diagnosis. Neither prior therapy, cytogenetic subgroup nor prior diagnosis influenced OS for t-ALL patients.When compared to de novo ALL, t-ALL patients were older (55 yrs vs. 37 yrs, p <0.01) with more female predominance (58% vs. 42%, <0.01), but there was no difference in initial WBC or leukemia phenotype. t-ALL cases were associated with more frequent Ph+ (32% vs. 26%) and MLL rearrangement (16% vs. 5%) but less normal karyotype (18% vs. 30%) when compared to de novo ALL (p<0.01). Patients with t-ALL more frequently reported immediate family history of malignancy (37% vs. 25%, p=0.01). CR rate was similar for t-ALL and de novo ALL (p=0.88) and the rate of HCT utilization during ALL therapy was not different (55% vs. 62%, p=0.22). However, 1-yr OS was inferior in t-ALL compared to de novo ALL cases (76% vs. 87%, p<0.01).In conclusion, we report the largest experience of t-ALL that restricts analysis to only cases with prior exposure to cytotoxic therapy. t-ALL was associated with unique features such as high frequency of Ph+ and MLL rearrangement as well as older age and female predominance. The latency period was shorter for patients carrying MLL gene rearrangement, similar to t-AML. Although CR rate and HCT utilization were similar for t-ALL and de novo ALL, OS was inferior for t-ALL patients. Molecular studies are warranted to further define t-ALL and determine if it has distinct genotypic features, and possibly differentiate it from de novo ALL that occurs coincidently in patients with prior chemotherapy exposure. [Display omitted] DisclosuresSalhotra:Kadmon: Consultancy. Khaled:City of Hope: Research Funding; Daiichi Sankyo, Inc: Other: Travel Support. Krishnan:Sutro: Consultancy; Onyx: Speakers Bureau; Takeda: Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Equity Ownership, Speakers Bureau. Stein:Stemline: Consultancy; Amgen: Consultancy, Speakers Bureau.

Clinical and Molecular Characteristics of Therapy-Related Acute Lymphoblastic Leukemia

Background: Therapy-related acute lymphoblastic leukemia (t-ALL) represents <7% of all ALL cases (Ganzel C, et al. 2015; 170:50-5). While treatment-related acute myeloid leukemia is more common and better described, our knowledge on t-ALL is limited. Furthermore, “secondary ALL” has been used as a broad term, combining patients with t-ALL and ALL patients with antecedent malignancy who did not receive chemotherapy or radiotherapy for the first malignancy (am-ALL). We investigated the clinical and molecular characteristics, as well as prognostic predictors of outcomes in t-ALL patients, while comparing t-ALL to am-ALL.Methods: ALL patients treated at the Cleveland Clinic, University of Washington, University of Chicago, and Stanford University during the years 1997-2016 were screened for eligibility. Patients with a history of another malignancy prior to ALL diagnosis were included, and further categorized as t-ALL and am-ALL based on the administration of chemotherapy or radiotherapy for first malignancy. Patients with mixed lineage leukemia and CML in blast crisis were excluded. Complete response (CR) was defined as <5% blasts with an absolute neutrophil count (ANC) of >1000/uL and platelets >100,000/uL; CRi: same as CR without count recovery. Cytogenetic risk was ascribed by CALGB criteria. A subset of diagnostic samples were sequenced with libraries prepared according to Illumina's Nextera Rapid Capture Custom Enrichment Kit and subjected to massive parallel sequencing using the HiSeq 2000. Our panel consisted of 170 genes highly prevalent in hematologic cancers or associated with congenital blood disorders.Results: A total of 82 patients with t-ALL, and 16 with am-ALL were identified. In the t-ALL group, 56.1% were female, 70.7% were Caucasian, 92.7% had B-ALL, and 47.3% had poor risk cytogenetics. The median age at ALL diagnosis was higher in the am-ALL group as compared to t-ALL (65 vs 58.5, respectively, p= 0.03), however the interval between the diagnosis of first malignancy and ALL was similar between the groups (7.5 vs 6.3 years, respectively, p= 0.34) (Table). In the t-ALL group, treatment for the first malignancy included alkylators in 64%, topoisomerase II inhibitors in 33%, and radiotherapy in 63%. The CR rate was significantly lower in patients with a history of radiotherapy (80% vs 100%, p= 0.003). Patients with t-ALL had a shorter median overall survival (OS) (23 vs 38 months, p= 0.33) and relapse-free survival (RFS) (11 vs 27 months, p=0.28) than patients with am-ALL, but the difference did not reach statistical significance (Figure). In univariable analysis, factors associated with worse outcomes in t-ALL patients included male sex (HR, 2.24; p= 0.009 for OS, and HR, 2.16; p=0.008 for RFS) and hematologic cancer history (HR, 2.14; p=0.03 for OS, and HR, 1.8; p= 0.06 for RFS), while Asian race (HR, 0.21; p= 0.04 for OS, and HR, 0.17; p= 0.01 for RFS) and performance of hematopoietic cell transplant (HCT) after ALL diagnosis (HR, 0.53; p= 0.04 for OS, and HR, 0.65; p= 0.15 for RFS) were associated with better survival. Other clinical factors analyzed, including age at ALL diagnosis, type of treatment for first malignancy, immunophenotype, and cytogenetics for ALL did not have a significant impact on survival. In multivariable analysis, longer interval between the first malignancy and ALL (HR, 0.93; p= 0.05 for OS, and HR, 0.94; p= 0.05 for RFS) and performance of HCT for ALL (HR, 0.44; p= 0.02 for OS, and HR, 0.61; p= 0.14 for RFS) were independent predictors of better outcomes in t-ALL. An expanded mutation panel was performed in 9 t-ALL and 3 am-ALL patients, for whom samples were available for sequencing. In the t-ALL group, all patients had at least one mutation: 3 patients had KDM6B , 2 patients had TP53 , and 2 patients had BRCA2 mutations. In am-ALL, 1 patient had JAK2 , and 1 patient had an NBN mutation.Conclusion: Therapy-related ALL is a rare complication of treatment for previous malignancies. While there is no significant difference in clinical features of t-ALL vs am-ALL, our observation on genomic characteristics of a small cohort of patients suggest that they might be biologically different. Longer interval between two diagnoses and performance of HCT after ALL were associated with better outcomes. We believe that our results improve our knowledge on this rare entity, and should be further validated through larger prospective studies utilizing comprehensive lymphoid mutation panels. [Display omitted] DisclosuresStock:Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Larson:Novartis: Consultancy, Research Funding; Amgen Inc.: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas: Consultancy, Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees. Gerds:Incyte: Consultancy; CTI BioPharma: Consultancy. Maciejewski:Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fees; Apellis Pharmaceuticals: Consultancy; Ra Pharma: Consultancy. Advani:Takeda/ Millenium: Research Funding; Pfizer: Consultancy.

Long Term Analysis of a Monocentric Cohort of Therapy-Related Acute Lymphoblastic Leukemia

Therapy related Acute Lymphoblastic Leukemia (t-ALL) refers to ALL developed in patients who have received prior cytotoxic therapies, including chemotherapies (CT) and/or radiotherapy (RT). Contrary to therapy-related myeloid neoplasms, t-ALL has not been fully recognized and its clinical and biological features remain poorly described. We reviewed all consecutive cases of adult t-ALL treated at our institution and described their clinical, phenotypic, and genetic characteristics. Between 1998 and 2019, 36 patients were admitted at Institut Paoli-Calmettes for t-ALL which represents 3.5% of all ALL admitted during the same period (n=1036). Median age was 67.5 years (ranges, 20-83). Twenty-eight (78%) patients were females. Thirty-eight (78%) patients of the t-ALL were secondary to a solid cancer. Among the most frequent solid tumors, we found 14 (39%) breast cancers, 5 (14%) pulmonary cancers and 4 (11%) thyroid cancers. Eight patients had a t-ALL secondary to a hematological malignancy (4 Non-Hodgkin lymphomas, 3 Hodgkin lymphomas and one myeloma). Three (8%) patients presented with more than one primary cancer. Primary malignancies were treated with CT in 7 cases (19%), RT in 11 cases (31%) and CT+RT in 16 cases (44%), in association or not with surgery of the primary tumor. Median time between the start of first malignancy treatment and t-ALL diagnosis was 5.4 years (ranges, 0.3-35). Median white blood cell count (WBC) was 15.9 (ranges, 0.6-386). Phenotypic characteristics at diagnosis were consistent with B-ALL for 31 patients (86%), and T-ALL or acute mixed-lineage leukemia for 2 (6%) and 3 (8%) patients, respectively. 9 (22%) cases were Philadelphia chromosome-positive by karyotype or Fluorescent in situ hybridization, 5 (14%) cases had MLL rearrangement, 5 (14%) cases had hypodiploidy, 3 (8%) cases had hyperdiploidy and 3 (8%) cases had normal karyotype. The 11 (30%) other cases had other genetic abnormalities. Thirty-one (86%) patients received intensive CT and 5 (14%) patients received a palliative treatment. For one patient, treatment modalities were missing. Twenty-eight (78%) were in complete remission (CR) after CT and 7 (19%) patients underwent an allogenic hematopoietic stem cell transplantation in first CR. Median follow-up was 52 months. Median overall survival calculated from the time of t-ALL diagnosis was 16 months and median leukemia-free survival was 14.3 months. Multivariate analyses taking age, WBC, MLL alteration, complex karyotype and BCR-ABL rearrangement into account, found that BCR-ABL alteration was associated with a higher OS (HR=4.9; ranges, 1.1-22.6). In conclusion, our results confirm that t-ALL is a rare event. Besides an older age at diagnosis, t-ALL does not display specific phenotypic or genetic characteristics. In our series, the patient outcome was poor. Further genetic studies are needed to better understand the pathogenesis of this ALL subgroup. Disclosures No relevant conflicts of interest to declare.

Therapy-related B-cell acute lymphoblastic leukemia in adults has unique genetic profile with frequent loss of TP53 and inferior outcome.

Therapy-related B-cell acute lymphoblastic leukemia in adults has unique genetic profile with frequent loss of TP53 and inferior outcome.

Outcomes of therapy-related acute lymphoblastic leukemia in adults after allogeneic stem cell transplantation.

Therapy-related acute lymphoblastic leukemia (t-ALL) is an increasingly recognized subset of therapy-related acute leukemia. There are limited data on the role of allogeneic hematopoietic stem cell transplantation (HSCT) in t-ALL. Recent reports suggest comparable outcomes of t-ALL with de novo ALL after HSCT. We retrospectively reviewed all patients of t-ALL who underwent HSCT at our center. Patients were analyzed for prior malignancy, therapy, time to diagnosis of t-ALL, clinical, laboratory characteristics, transplant details, relapse-free survival (RFS), and overall survival (OS). Eighteen patients (M:F ratio 1:1; Median age 44years) underwent HSCT for t-ALL. Median latent period from primary malignancy to t-ALL was 44.8months. 11q23 rearrangement and t(9;22) were present in 33.3% and 22.2% patients, respectively. Stem cell donors were matched related, matched unrelated, and haploidentical in 27.8% (n=5), 55.6% (n=10), and 16.7% (n=3) patients, respectively. Five patients died before D+ 100 (27.8%). Estimated 2-year RFS and OS were 47.1% and 51.8%, respectively. We did not find any pretransplant and post-transplant risk factors that were predictive of improved OS or RFS after multivariate analysis. Allogeneic HSCT outcomes in t-ALL were comparable to HSCT outcomes in de novo ALL. Multicenter studies with more patients and longer follow-up may provide factors affecting outcome and survival.

Therapy-related acute lymphoblastic leukemia is a distinct entity with adverse genetic features and clinical outcomes

AbstractPatients with therapy-related acute lymphoblastic leukemia (t-ALL) represent a small subset of acute lymphoblastic leukemia (ALL) patients who received genotoxic therapy (ie, chemotherapy or radiation) for a prior malignancy. These patients should be distinguished from patients with de novo ALL (dn-ALL) and ALL patients who have a history of prior malignancy but have not received cytotoxic therapies in the past (acute lymphoblastic leukemia with prior malignancy [pm-ALL]). We report a retrospective multi-institutional study of patients with t-ALL (n = 116), dn-ALL (n = 100), and pm-ALL (n = 20) to investigate the impact of prior cytotoxic therapies on clinical outcomes. Compared with patients with pm-ALL, t-ALL patients had a significantly shorter interval between the first malignancy and ALL diagnosis and a higher frequency of poor-risk cytogenetic features, including KMT2A rearrangements and myelodysplastic syndrome-like abnormalities (eg, monosomal karyotype). We observed a variety of mutations among t-ALL patients, with the majority of patients exhibiting mutations that were more common with myeloid malignancies (eg, DNMT3A, RUNX1, ASXL1), whereas others had ALL-type mutations (eg, CDKN2A, IKZF1). Median overall survival was significantly shorter in the t-ALL cohort compared with patients with dn-ALL or pm-ALL. Patients who were eligible for hematopoietic cell transplantation had improved long-term survival. Collectively, our results support t-ALL as a distinct entity based on its biologic and clinical features.

Clinical characteristics and prognosis of 35 patients with therapy-related hematological neoplasms

目的探讨治疗相关血液肿瘤的临床特征及预后。方法采用细胞形态学、流式细胞术、间期荧光原位杂交技术（I-FISH）、染色体核型分析对35例治疗相关血液肿瘤患者进行诊断和分型并回顾性分析其临床特征及预后。结果35例患者中，治疗相关急性髓系白血病（t-AML）20例，治疗相关急性淋巴细胞白血病（t-ALL）4例，治疗相关急性混合细胞白血病1例，治疗相关非霍奇金淋巴瘤（t-NHL) 8例，治疗相关骨髓增生异常综合征（t-MDS）2例。第一肿瘤至治疗相关恶性血液肿瘤的中位发病间隔期为29(16~90）个月，中位生存时间14(1~60）个月，3年累积生存率为17.1%。在25例治疗相关性急性白血病患者中，40.0%（10/25）合并复杂核型，36.0%（9/25）合并MLL断裂基因重排，12.0%（3/25）合并AML-ETO融合基因阳性，1例合并NPM1点突变，1例合并P16基因缺失。结论治疗相关血液肿瘤患者的预后差。

Patients over Age 40 with Ph-Negative Acute Lymphoblastic Leukemia Do Not Benefit from Allogeneic Transplant in First Remission. Retrospective Analysis from a Large Tertiary Center

Background: Survival of adult patients with Ph-negative acute lymphoblastic leukemia (ALL) with conventional therapeutic approaches remains poor. Given the ability to safely perform allogeneic stem-cell transplant (alloSCT) in this age cohort, older patients with ALL in first complete remission (CR1) are increasingly offered consolidation with this modality. We asked whether alloSCT in CR1 offers a survival advantage in older patients with ALL as compared to post remission chemotherapy.Methods: One hundred and seven patients ≥40 years were treated at the Dana Farber Cancer Institute for Ph-negative ALL from 1/1/2006 to 12/31/2013; of the 99 patients treated with curative intent, 80 patients (age 54.5 years; range 41-83) achieved first remission (81%; CR and CRi). Baseline characteristics of the chemotherapy and alloSCT post remission groups were compared using the Fisher exact and Wilcoxon rank-sum tests for categorical and continuous variables, respectively. The comparison of outcomes between the alloSCT and chemotherapy cohorts was made using a modified Mantel-Byar test to account for the waiting time to transplant. For graphical comparisons, the method of left-truncation was used to adjust for the time of wait from first CR/CRi to transplant. In Cox modeling of overall survival (OS) and disease free survival (DFS), treatment was included as a time-dependent variable. The cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were calculated and compared between groups from the time of CR/CRi to the time of the event with each considered as competing events. Retrospectively determining the reason for choosing one post remission approach over the other was not always possible. Furthermore, MRD status was available in a minority of patients. The effect and relation of these factors to patient selection and outcome therefore could not be assessed.Results: Eighty patients in first CR/CRi were analyzed. B-cell ALL was diagnosed in 86% of patients and T-cell origin was identified in 14% of patients; 6% of patients had therapy-related ALL. Median WBC, platelet and Hb levels at diagnosis were 5.3X109/L, 61X109/L and 9.6mg/dL, respectively. Cytogenetics were available for 63 patients (cytogenetics were not reported for referred patients (n=11) or were unsuccessful (n=6)) and were diploid (52%), near hyperploid (25%), hyperploid (11%), near hypoploid (5%) and hypoploid (2%). MLL rearrangement was identified in 12.5% of patients. Most patients had an ECOG performance status of 0-1; the median modified Charlson co-morbidity index score was 2 (range 0-10) and 56% of patients had ≥1 co-morbidities.In the alloSCT group, myeloablative and reduced-intensity conditioning were used in 55% and 45% of patients, respectively. Matched related and matched unrelated donors were used in 40% and 48% of patients, respectively, with the remainder receiving alternative donor sources.Forty patients received alloSCT in first remission and 40 patients were treated with chemotherapy only. Baseline characteristics did not significantly differ between the 2 groups except for lower Hb in the alloSCT group (p=0.028). Nine of 10 patients with MLL rearrangement were allocated to the alloSCT group.The median follow-up in the alloSCT and chemotherapy groups was 3.7 and 2.6 years, respectively. OS (Figure 1) and DFS did not differ between the groups at 3 years; the significantly higher CIR rate in the chemotherapy group was offset by the higher NRM in the alloSCT group (Table 1).Univariate Cox Modeling of 13 patient, disease and treatment-related factors including post remission modality were analyzed, none of which were shown to affect OS or DFS. WBC at diagnosis (≥20K vs. <20K) achieved borderline significance for DFS (p=0.053). The type of conditioning and donor source did not affect survival within the alloSCT group.Conclusion: AlloSCT in first CR is associated with a lower CIR but this benefit is offset by higher NRM as compared to chemotherapy. Although this should be confirmed in larger cohorts, these data suggest that alloSCT does not confer a survival benefit in patients ≥40 years with Ph-negative ALL.Table 1Outcome by CohortsOutcomeChemotherapy in CR1 (n=40)AlloSCT in CR1 (n=40)P-valueMedian Follow-up (years)2.6 (0.2, 8.2)3.7 (1.2, 7.0)0.223-yr % OS [95% CI]46 [31-68]39 [26-59]0.353-yr % DFS [95% CI]31 [18-52]40 [27-59]0.983-yr CIR %61 [41-76]28 [15-43]0.0113-yr NRM %9 [2-21]32 [17-47]0.014 [Display omitted] DisclosuresSteensma:Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy. Stone:Agios: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; AROG: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Juno: Consultancy; Novartis: Research Funding; Abbvie: Consultancy; Celator: Consultancy; Roche/Genetech: Consultancy; Amgen: Consultancy; Karyopharm: Consultancy; Merck: Consultancy.

Therapy-related B-lymphoblastic leukemia associated with Philadelphia chromosome and MLL rearrangement: Single institution experience and the review of the literature.

Therapy related acute lymphoblastic leukemia (t-ALL) of B cell origin is rare and constitutes approximately 2% of all ALL. Previously compiled data on the complete cytogenetic analysis of 48 t-B-ALL cases suggested that MLL rearrangement at 11q23 gene locus is the most common abnormality. Philadelphia chromosome (Ph) and a normal karyotype were reported as the second and third most common karyotypes, respectively. We investigated cytogenetic karyotypes of six t-B-ALL cases with a pre-B cell immunophenotype. Ph + t-B-ALL was noted in four of six patients previously treated with radiation and/or chemotherapy. In addition, one case demonstrated MLL rearrangement at 11q23 locus while one case demonstrated normal cytogenetic karyotype. Five of the six t-B-ALL patients had persistent leukemia following initiation of chemotherapy for secondary leukemia with survival ranging from 10 to 21 months. To our knowledge, only fourteen patients with Ph + t-B-ALL have been described in the literature. In the current study, three of four cases with Ph + t-B-ALL were associated with treated breast carcinoma while one patient was treated for Hodgkin lymphoma. All four patients had undergone radiation therapy. The results may indicate a plausible association between Ph+t-B-ALL and prior radiation exposure.

Therapy-Related Acute Lymphoblastic Leukemia: Cytogenetic Features and Hematopoietic Cell Transplantation Outcome

The clinical and pathologic characteristics and treatment outcome of therapy-related acute lymphoblastic leukemia (t-ALL) remains less defined compared to therapy-related acute myeloid leukemia. Although MLL rearrangement is the most characteristic genetic abnormality associated with t-ALL, other chromosomal alterations have been described.We examined the pathologic features and treatment outcome of a cohort of t-ALL patients who were undergoing allogeneic hematopoietic cell transplantation (HCT) in order to better define the cytogenetic profile of t-ALL, and to determine the outcome of t-ALL with allogeneic HCT. We reviewed all consecutive cases of adult ALL that had undergone allogeneic HCT at our institution between 1998 and 2014. Data on previous malignancy, chemotherapy, radiation, cytogenetic abnormalities and survival were collected and analyzed.We identified 28 cases of t-ALL who had history of chemotherapy and/or radiation prior to ALL diagnosis and subsequently undergone allogeneic HCT at our institution. The median age was 48 years (range 29-61), and 57% of patients were female. The most common prior diagnosis was breast cancer (n=9), followed by multiple myeloma (n=4), sarcoma (n=4), thyroid cancer/disease (n=4), lymphoma (n=3), germ cell tumor (n=2, including a case of combined germ cell and CLL), melanoma (n=1), and colon cancer (n=1). The median interval from initial diagnosis of malignancy to diagnosis of t-ALL was 7.3 years (range; 0.9-50.7). Thirty-nine percent had prior combination of chemotherapy and radiation therapy, 32% had prior radiotherapy alone and 29% had prior chemotherapy alone. Four patients had undergone autologous-HCT prior to t-ALL onset. All cases had B-cell phenotype. Median initial WBC was 8 X 109/L (range 1.2-323). Interestingly, in our cohort the most common cytogenetic abnormality was t(9;22) [Philadelphia chromosome] (39%), and followed by MLL rearrangement (25%). The median interval from diagnosis of previous malignancy to ALL diagnosis was 9.3 years for Ph+ ALL, 2.1 years for MLL-rearranged ALL, and 7.9 years for other cytogenetic types of t-ALL. The median initial WBC on presentation was 8 X 109/L for Ph+ ALL, 17 X 109/L for MLL-rearranged ALL, and 8 X 109/L for other cytogenetic types of t-ALL. Disease status at the time of HCT was as follows: 20 patients were in CR1, 2 were in CR2, 3 were in first relapse and another 3 after induction failure. Conditioning regimen was full intensity in 16 patients and reduced intensity in 12. Four-year Leukemia-free survival (LFS) and overall survival (OS) for the whole cohort were 46% and 49%, respectively. The 4-year LFS and OS for MLL-rearranged cases, Ph+ cases and other cytogenetic types were (62% vs. 43% vs. 40%, p=0.68) and (60% vs. 56% vs. 35%, p=0.71), respectively. In this cohort, only one patient relapsed with the original disease (CLL) after allogeneic HCT. The 100 days non-relapse mortality for evaluable patients was 8%.Ph+ t-ALL is an under recognized subtype of t-ALL and appears to be at least as common as MLL rearrangement among t-ALL. The HCT outcome of t-ALL appears to be similar to de novo ALL. DisclosuresNo relevant conflicts of interest to declare.

Precursor B-Cell Acute Lymphoblastic Leukemia in Two Patients with a History of Cytotoxic Therapy

Therapy-related myeloid neoplasms have been well characterized. However, precursor B-cell acute lymphoblastic leukemia in patients with prior malignancies is uncommon, and the effect of prior cytotoxic therapy on development of precursor B-cell acute lymphoblastic leukemia is controversial. Therapy-related precursor B-cell acute lymphoblastic leukemia has been reported occasionally. However, cytotoxic therapy-related precursor B-cell acute lymphoblastic leukemia has been reported in Korea only rarely. We herein describe two cases of therapy-related precursor B-cell acute lymphoblastic leukemia. (Korean J Med 2013;85:96-100)

Therapy-related pro-B cell acute lymphoblastic leukemia: report of two patients with MLL amplification

Improvements in chemotherapy and medical support of patients treated with chemotherapy and radiation have led to an ever-increasing number of cancer survivors. Unfortunately, a small fraction of these patients develop secondary hematologic malignancies as a consequence of their exposure to genotoxic anti-cancer regimens. Most of these are myeloid malignancies, therapy-related acute myeloid leukemia (t-AML) or myelodysplasia (t-MDS); however, a small but growing body of literature exists, which describes therapy-related acute lymphoblastic leukemias (t-ALL). Nearly all these cases are reportedly associated with translocations involving chromosome 11q23, the site of the MLL gene. We herein report two cases of ALL occurring after chemotherapy for other malignancies that showed complex karyotypic abnormalities and distinct MLL amplification by fluorescence in situ hybridization analysis. Immunophenotypic analysis showed that both cases expressed a pro-B cell (CD10-) phenotype with aberrant myeloid antigen expression. Although MLL amplification has been reported in therapy-related myeloid disease, to our knowledge this is the first report of MLL amplification occurring in therapy-related B cell ALL.

Therapy‐related acute lymphoblastic leukemia is more frequent than previously recognized and has a poor prognosis

Acute lymphoblastic leukemia (ALL) occurring in patients with a history of prior chemotherapy/radiotherapy exposure has been previously reported to be rare, accounting for <2.5% of ALL cases. All cases of adult ALL with a history of prior cytotoxic or radiation therapy at a leukemia referral center over a 13-year period were analyzed. Twenty-three cases, representing 6.9% of all ALL cases, were identified. Of these, 17 (74%) had at least 1 high-risk feature; 8 (35%) had MLL rearrangements, and 4 were BCR-ABL(+) . MLL rearrangements were correlated with CD15 expression and absence of CD10, and also tended to have a shorter mean latency period and more prior topoisomerase II exposure. Twenty-one patients received induction therapy, and 18 (86%) achieved a complete response, 17 with 1 induction. Six patients have relapsed and died, and 4 others died of other complications, 2 of these postallogeneic stem cell transplantation. Median disease-free survival (DFS) and overall survival (OS) were 27 and 13.6 months, respectively, and 3-year DFS and OS were 37.1% and 37.6%, respectively. The frequency of therapy-related ALL is higher than previously reported and has a poor prognosis, probably related to the high frequency of adverse risk features.

Therapy-Related Pro-B Cell Acute Lymphoblastic Leukemia: Report of Two Patients with MLL Amplification

Abstract 4911Recent advances in cancer treatment have led to an ever increasing number of cancer survivors. Unfortunately, a small fraction of these patients develop secondary hematologic malignancies as a consequence of their exposure to genotoxic anti-cancer regimens. Most of these are myeloid malignancies, therapy-related acute myeloid leukemia (t-AML) or myelodysplasia (t-MDS). Current classification schemes separate therapy-related myeloid disorders into two classes, those related to prior exposure to alkylating agents or radiation and those with prior exposure to DNA topoisomerase II inhibitors. The alkylating/radiotherapy group often contain chromosomal abnormalities involving chromosomes 5 and 7. In contrast, those with DNA topoisomerase II inhibitor exposure frequently possess chromosomal translocations involving chromosome 11q23, where the MLL gene locus resides. MLL, or “mixed lineage leukemia”, is also frequently rearranged in lymphoblastic leukemias and mixed phenotype acute leukemias. Interestingly, MLL also can be altered in myeloid disease through partial tandem duplication or amplification of the genomic region encompassing MLL [amp(MLL)]. Amp(MLL) of an unrearranged MLL locus has also been described in therapy-related myeloid disease.Recently, there has been a growing appreciation that therapy-related leukemias are not limited to the myeloid lineage and that therapy-related acute lymphoblastic leukemias (t-ALL) make up a small but significant percentage of therapy-related acute leukemias. Translocations involving the MLL locus have been found in a high percentage of t-ALLs. However, to our knowledge, amp(MLL) has not been reported previously in t-ALL. Herein we report 2 cases of ALL following chemotherapy for other malignancies that showed complex karyotypic abnormalities and distinct MLL amplification by FISH analysis.Patient 1 is an 80 year old male with a past medical history significant for a stage IV diffuse large B cell lymphoma two years prior. The patient received 8 cycles of R-CHOP chemotherapy and achieved a complete remission. One year later, he had a recurrence and was treated with 7 cycles of RICE chemotherapy. Eleven months later, he presented with leukopenia. A bone marrow examination revealed involvement by B cell ALL. Cytogenetic analysis showed a hypodiploid complex karyotype which included a homogeneously staining region (hsr) at chr11(q23). Metaphase FISH analysis showed amp(MLL) in the hsr.Patient 2 is a 62 year old male who five years prior had been diagnosed with a pleiomorphic sarcoma of the left hip. The patient received four cycles of doxorubicin and ifosfamide as well as radiation therapy. The patient remained well for five years but then presented with bleeding and a petechial rash. A complete blood count revealed anemia and thrombocytopenia. A bone marrow examination was performed which showed involvement by B cell ALL. Cytogenetic analysis showed multiple numerical and structural abnormalities including an hsr at chr11(q23) in all lines as well as a second hsr in two sidelines. Metaphase FISH analysis showed amp(MLL) in all cells and in both hsrs. Immunophenotypic analysis showed both cases to express a Pro-B cell (CD10-) phenotype with aberrant myeloid antigen expression.Frequent molecular perturbation makes the MLL locus one of the most common genetic targets in hematologic malignancies, particular in therapy-related neoplasms. The majority of MLL genetic alterations result in translocations involving the MLL gene. These translocations result in fusion proteins with heterologous functions of MLL that result in a block of differentiation. Similarly, amp(MLL), while not creating an abnormal fusion protein involving MLL, also is considered to be a “gain of function” mutation caused by increased expression of MLL. There seems to be an increased frequency of aml(MLL) in therapy-related myeloid disorders.In summary, we report, to our knowledge, the first cases of therapy-related pro B cell (CD10-) ALL associated with amp(MLL). The shared phenotype between B cell ALLs with MLL rearrangements and amp(MLL) suggests that both lesions may exert similar influences on the transcriptional programs of these leukemias. This observation extends the family of MLL-associated and therapy-related hematologic disorders. Disclosures:No relevant conflicts of interest to declare.

Therapy-related acute lymphoblastic leukemia with t(4;11)(q21;q23) masqueraded as marrow lymphocytosis in a patient with breast cancer

Therapy-related acute leukemia develops in patients after chemotherapy and/or radiotherapy for a prior cancer, and most cases are acute myeloid leukemia with a much lower frequency of acute lymphoblastic leukemia (ALL). One unique feature of these therapy-related ALL (t-ALL) is an increased incidence of chromosome band 11q23 aberrations as compared with de novo ALL. In adult female patients, breast cancer is the most common primary cancer. Herein, we report the case of a 49-year-old Taiwanese lady who developed t-ALL with t(4;11)(q21;q23) 16 months after cyclophosphamide, epirubicin, and 5-fluorouracil chemotherapy for her breast cancer. The unusual feature is that the t-ALL was heralded 4 months ago by marrow lymphocytosis comprising atypical small lymphocytes with condensed chromatin mimicking a B-cell chronic lymphoproliferative disorder. Retrospective studies using additional antibodies for immunophenotyping and PCR-based clonality study for immunoglobulin gene rearrangement showed that these atypical small lymphocytes shared similar features with the leukemic blasts at the frank leukemic stage. Our results suggest that these atypical small lymphocytes are lymphoblasts in disguise and that the clinicopathological correlations with ancillary pathological studies are important to reach a definitive diagnosis of such an unusual case.