Therapy-related Acute Leukemia Research Articles

Therapy-related acute lymphoblastic leukaemia in women with antecedent breast cancer.

Therapy-related acute lymphoblastic leukaemia (tr-ALL) is a disease entity attributed to previous exposure to chemotherapy and/or radiation for antecedent malignancy. There is observed female predominance for tr-ALL, likely due to high prevalence and excellent curable rate for non-metastatic breast cancer as well as the frequent use of carcinogenic agents as part of adjuvant therapy. Here, we reviewed 37 women with diagnosis of ALL following breast cancer treatment with focus on cytogenetic categorization. Philadelphia chromosome positivity (Ph+), KMT2A alterations and other cytogenetic change groups were observed in 32%, 22% and 46% of patients respectively. Median overall survival (OS) and relapse-free survival (RFS) were 19.4 and 12.9 months, overall while both OS and RFS were superior in tr-ALL with Ph+ disease compared to KMT2Ar and other cytogenetics respectively. Seventeen (45.9%) patients underwent consolidative allogeneic haematopoietic cell transplantation (alloHCT) in CR1 out of which 4 (24%) relapsed following transplant. Both OS and RFS were superior in the KMT2Ar cytogenetics group following alloHCT. Ph chromosome represents the largest genetic entity of tr-ALL following breast cancer therapy, and it may be associated with superior survival outcomes while KMT2Ar may be associated with poorer outcomes that can perhaps be mitigated by alloHSCT.

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.

Chronic myeloid leukaemia in blast phase with t(9;11)(p21;q23), KMT2A::MLLT3 gene fusion

Case: A 51-year-old man presented with lymphadenopathy and increasing fatigue. He had been diagnosed with chronic myeloid leukaemia (CML) seven months earlier and had a suboptimal response to first line nilotinib, failing to achieve MR1 with BCR-ABL1/ABL persistently >10% (IS). A repeat bone marrow examination showed 90% blasts, consistent with CML in blast phase (CML-BP). The blasts showed monoblastic morphology and immunophenotype. Conventional karyotype showed both t(9;22)(q34;q11.2), involving the long arm of chromosome 9, and t(9;11)(p21;q23), involving the short arm of the same derivative chromosome 9. FISH confirmed KMT2A breakapart. A core biopsy of cervical lymph node demonstrated a monoblastic leukaemic infiltrate and BCR-ABL1 mutational analysis did not identify any resistance mutations. Discussion: Progression of CML to accelerated or blast phase is usually accompanied by a series of genomic events including BCR-ABL1 resistance mutations, other somatic mutations and additional cytogenetic abnormalities (ACAs). Common ACAs include extra Philadelphia chromosome, trisomy 8, trisomy 9 and isochromosome 17q. KMT2A rearrangement involving the 11q23 locus are common in de novo or therapy related acute leukaemia (both myeloid and lymphoid), but rarely reported in CML blast phase (<1%). The few reported cases show an aggressive clinical presentation, poor outcomes and poor response to tyrosine kinase inhibitors (TKI).

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

Therapy-related acute myeloid leukemia: A case series.

Patients with primary cancer receiving chemotherapy and/or radiotherapy may develop therapy-related acute leukemia (t-AL). Therapy-related acute myeloid leukemia (t-AML) accounts for the majority of these cases and is frequently associated with a variety of cytogenetic and molecular abnormalities. The aim of the present study was to explore the clinical characteristics, treatments and prognosis of patients with t-AML. A total of 272 cases of AML treated at our institution between 2016 and 2020 were reviewed, among which nine cases of t-AML were identified for analysis. All patients had received alkylating or topoisomerase II inhibitor chemotherapy drugs for primary cancer treatment and three patients had received radiotherapy. A total of nine patients had been administered recombinant human granulocyte colony-stimulating factor (G-CSF). The median latency period for the nine patients with t-AML was 25 months (range, 10–240 months). The molecular cytogenetic abnormalities included t(15:17)(q22:q21), inv(16)(p13q22), del(5)(q22), CBFB/MYH11(+), FLT3(+), NARS(+), IDH(+), TET2(+), and TP53(+). Out of nine patients with t-AML, eight received chemotherapy, two of whom underwent HSCT. The median survival time of the nine patients with t-AML was 10 months and the 2-year-survival rate was 44.4%. Greater clarity around the diagnosis and treatment is required to improve the outcomes of patients with t-AML.

Therapy Related Chronic Myeloid Leukemia – A Case Report

Therapy-related acute leukemia or myelodysplastic syndrome are well-recognized entities, whereas less is known about the incidence of secondary chronic myeloid leukemia (CML) after cytotoxic treatments, particularly radiotherapy, for a primary malignancy. Here we report a patient who was initially treated 8 years before with concurrent chemoradiation followed by High Dose Rate (HDR) Brachytherapy for FIGO Stage IIB carcinoma cervix, and now while on follow up developed CML. Keywords: Chronic myeloid leukemia, Cervical cancer, second malignancies, therapy related.

Bone Marrow Surveillance of Pediatric Cancer Survivors Identifies Clones that Predict Therapy-Related Leukemia.

Therapy-related myelodysplastic syndrome and acute leukemias (t-MDS/AL) are a major cause of nonrelapse mortality among pediatric cancer survivors. Although the presence of clonal hematopoiesis (CH) in adult patients at cancer diagnosis has been implicated in t-MDS/AL, there is limited published literature describing t-MDS/AL development in children. We performed molecular characterization of 199 serial bone marrow samples from 52 patients treated for high-risk neuroblastoma, including 17 with t-MDS/AL (transformation), 14 with transient cytogenetic abnormalities (transient), and 21 without t-MDS/AL or cytogenetic alterations (neuroblastoma-treated control). We also evaluated for CH in a cohort of 657 pediatric patients with solid tumor. We detected at least one disease-defining alteration in all cases at t-MDS/AL diagnosis, most commonly TP53 mutations and KMT2A rearrangements, including involving two novel partner genes (PRDM10 and DDX6). Backtracking studies identified at least one t-MDS/AL-associated mutation in 13 of 17 patients at a median of 15 months before t-MDS/AL diagnosis (range, 1.3-32.4). In comparison, acquired mutations were infrequent in the transient and control groups (4/14 and 1/21, respectively). The relative risk for development of t-MDS/AL in the presence of an oncogenic mutation was 8.8 for transformation patients compared with transient. Unlike CH in adult oncology patients, TP53 mutations were only detectable after initiation of cancer therapy. Last, only 1% of pediatric patients with solid tumor evaluated had CH involving myeloid genes. These findings demonstrate the clinical relevance of identifying molecular abnormalities in predicting development of t-MDS/AL and should guide the formation of intervention protocols to prevent this complication in high-risk pediatric patients.

Therapy-related Acute Lymphoblastic Leukaemia has a Unique Genetic Profile Compared to De Novo Acute Lymphoblastic Leukaemia.

Background: Unlike therapy-related myeloid neoplasms, therapy-related acute lymphoblastic leukaemia (tr-ALL) is poorly defined due to its rarity. However, increasing reports have demonstrated that tr-ALL is a distinct entity with adverse genetic features and clinical outcomes.Methods: We compared the clinicopathological characteristics and outcomes of patients diagnosed with tr-ALL (n = 9) or de novo ALL (dn-ALL; n = 162) at a single institution from January 2012 to March 2021. The mutational landscapes of eight tr-ALL and 63 dn-ALL patients were compared from a comprehensive next-generation sequencing panel.Results: All tr-ALL patients had the B-cell phenotype. The most frequently mutated genes were IKZF1 (37%), CDKN2A (14%), SETD2 (13%), and CDKN2B (11%) in dn-ALL, whereas TP53 (38%) and RB1 (25%) mutations were most common in tr-ALL. tr-ALL patients did not show a statistically significant difference in overall survival (p = 0.70) or progression-free survival (p = 0.94) compared to dn-ALL patients.Conclusions: In this study, we determined the clinical and genetic profiles of Korean patients with tr-ALL. We found alterations in genes constituting the TP53/RB1 pathway are more frequent in tr-ALL. Due to the rarity of the disease, multi-institutional studies involving a larger number of patients are required in future study.

Allogeneic Transplantation to Treat Therapy-Related Myelodysplastic Syndrome and Acute Myelogenous Leukemia in Adults

Allogeneic Transplantation to Treat Therapy-Related Myelodysplastic Syndrome and Acute Myelogenous Leukemia in Adults

A rare der(10)t(X;10)(p11.2;p11.2) in an elderly patient with therapy-related acute myelomonocytic leukemia.

An 80-year-old male was referred to our hospital with dyspnea on effort. He had a history of diffuse large B-cell lymphoma 2 years ago, for which he was treated with chemotherapy, including rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone. His laboratory data included a white blood cell count of 1.9 × 109/L, a hemoglobin concentration of 10.5 g/dl, and a platelet count of 92 × 109/L. His serum lactate dehydrogenase level was 196 U/L. A bone marrow examination revealed a hypercellular bone marrow with a blast frequency of 23.4%. The blast cells were positive for both nonspecific esterase and naphthol AS-D chloroacetate esterase staining (Figure 1). A cytogenetic study of the patient's bone marrow cells demonstrated the following karyotype: 47,XY, +8, der(10)t(X;10)(p11.2;p11.2)[7]/46,XY[13] (Figure 2). A diagnosis of therapy-related acute myelomonocytic leukemia was made due to his history of chemotherapy-treated lymphoma. Although the patient received two courses of azacitidine monotherapy, it was not effective, and he died 3 months after being diagnosed with leukemia. To the best of our knowledge, only five cases of acute myeloid leukemia (AML) involving a translocation consisting of 10p11 and Xp11 breakpoints have been reported [1-5]. Of these, one case demonstrated the t(X;10)(p11;p11) translocation as a sole abnormality [3]. This translocation has never been reported in other solid tumors. Hence, t(X;10)(p11;p11) is considered to be a rare, but recurrent, cytogenetic aberration in AML. The reported cases have several things in common, that is, they all involved balanced translocations, most of them involved therapy-related leukemia, and all of the patients except one (a 50-year-old [5]) were children. Although our case also involved therapy-related leukemia, it was very rare, as it involved an 80-year-old patient who harbored an unbalanced der(10)t(X;10)(p11;p11) translocation. As for the association between t(X;10)(p11;p11) and the pathogenesis of AML, our case involved der(10)t(X;10)(p11;p11), but lacked der(X)t(X;10)(p11;p11) due to the unbalanced nature of the translocation. Therefore, der(10)t(X;10)(p11;p11), rather than der(X)t(X;10)(p11;p11), is proposed to play a crucial role in the leukemogenesis in t(X;10)(p11;p11)-harboring AML. The patient's consent was obtained for the publication of the case report. The authors declare no conflict of interest. Masahiro Manabe, Nao Tanizawa, Satoru Nannno, and Ki-Ryang Koh designed the study. Masahiro Manabe, Yuuji Hagiwara, and Reiko Asada analyzed the data. Masahiro Manabe and Ki-Ryang Koh collected the clinical data and specimens. Masahiro Manabe, Yuuji Hagiwara, and Reiko Asada wrote the manuscript. All of the authors have reviewed and approved the final manuscript. All data generated during this study are included in this manuscript.

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)

Immunologic Autograft Engineering: 13 Years Follow-up

Our group published a double blind, randomized phase III study (Porrata et al, BBMT 2016; 22: 1017-1023) showing that the infusion of autograft absolute lymphocyte count (A-ALC) ≥ 0.5 x 10 9 cells/kg is a survival prognostic factor for lymphoma patients undergoing autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT). However, a limitation of the study was the short-term follow-up duration of two years post-APBHSCT. To assess if the A-ALC still provide survival benefit we looked at the 121 lymphoma patients enrolled in the phase III from December 10, 2007 until October 12, 2010 survival outcomes with a longer follow-up duration of up to 13 years post-APBHSCT. Since the accrual for the study, 52 patients had died of recurrence lymphoma, 4 patients of therapy-related acute myelogenous leukemia, 3 patients of unknown causes, 1 patient of acute respiratory distress syndrome, 1 patient of anaplastic astrocytoma, and 1 patient of septic shock. The current median follow-up is 86 months (range: 2.1-158.1 months) for the entire cohort and 127.8 months (range: 5.9-158.1 months) for patients still alive. Patients infused with an A-ALC ≥ 0.5 x 10 9 cells/kg continue to experience superior overall survival (OS) (HR = 0.392, 95%CI 0.224-0.687, P < 0.001) and progression-free survival (PFS) (HR = 0.413, 95%CI 0.253-0.677, P < 0.0004). The 10-year OS rates for the A-ALC ≥ 0.5 x10 9 cells/kg patients was 70% (95% confidence interval [CI], 55%-81%) and for the A-ALC < 0.5 x10 9 cells/kg patients was 36% (95% CI, 25%-49%) (Figure 1A). The 10-year PFS rates for the A-ALC ≥ 0.5 x10 9 cells/kg group was 57% (95% CI, 43%-70%) and for the A-ALC < 0.5 x10 9 cells/kg group was 28% (95% CI, 19%-40%) (Figure 1B). Autograft lymphocyte subset analysis including autograft-CD3 (A-CD3), autograft CD4 (A-CD4), autograft CD8 (A-CD8), and autograft natural killer cells (A-NK), showed that the infusion of A-NK was a predictor for OS (HR = 0.518, 95%CI 0.292-0.919, P < 0.02) and PFS (HR = 0.393, 95%CI 0.230-0.670, P < 0.0006). The 10-year OS rates for the A-NK ≥ 0.09 x10 9 cells/kg patients was 67% (95% confidence interval [CI], 50%-80%) and for the A-NK < 0.09 x10 9 cells/kg patients was 42% (95% CI, 31%-54%) (Figure 1C). The 10-year PFS rates for the A-NK ≥ 0.09 x10 9 cells/kg group was 59% (95% CI, 43%-73%) and for the A-NK < 0.09 x10 9 cells/kg group was 32% (95% CI, 23%-44%) (Figure 1D). Both the A-ALC and A-NK were independent predictor for OS [ A-ALC: HR = 0.367, 95%CI 0.195-0.690, P < 0.001) and A-NK: HR = 0.411, 95%CI 0.275-0.892, P < 0.01] and for PFS [ A-ALC: HR = 0.477, 95%CI 0.271-0.840, P < 0.01) and A-NK: HR = 0.490, 95%CI 0.266-0.903, P < 0.02]. With a longer follow-up of 13 years, this study shows that the infusion of A-ALC continues to provide better clinical outcomes to lymphoma patients undergoing APBHSCT. These study findings support our standard practice changed of not only collecting CD34 stem cell for hematologic engraftment, but also A-ALC for lymphoma patients undergoing APBHSCT to improve clinical outcomes. Further, autograft immune effector studies are warranted such as A-NK to develop a more immunocompetent targeted autologous graft verus tumor effect. [Display omitted] DisclosuresAnsell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Paludo: Karyopharm: Research Funding.

Therapy-Related Mixed Phenotype Acute Leukemia: Report of two cases with clinicopathological and molecular data

Abstract Introduction/Objective Therapy-related mixed phenotype acute leukemia (Tr-MPAL) is a rare and aggressive disease comprising blast cells of more than one hematopoietic cell lineage. There is limited patient outcome data with this diagnosis. Hence, we present two such cases with clinicopathologic correlation. Methods/Case Report Clinical and pathology data were obtained from institutional electronic health records for two cases of Tr-MPAL identified in the past three years (2018-2020). Results (if a Case Study enter NA) Case 1: 60-years old female, history of chemo-radiotherapy for breast carcinoma, had 49% circulating dimorphic blasts. By immunophenotype, blasts were positive for CD34, CD117, HLA-DR, cCD3, TdT, CD13, CD15, CD38, CD2, CD7, and MPO by cytochemistry, negative for B-cell lineage markers, consistent with Tr-MPAL, T/Myeloid. Ancillary studies revealed normal female karyotype, FLT3-ITD positivity, and DNMT3A frameshift mutation. The patient achieved remission with ALL regimen Hyper-CVAD/methotrexate-cytarabine and underwent an allogeneic stem cell transplant (SCT). The patient was disease-free and on maintenance therapy post 2 years of initial diagnosis. Case 2: 49-years old female, history of chemotherapy for breast carcinoma, had 77% circulating dimorphic blasts (MPO+/PAX5- and MPO-/PAX5+/CD79a+). By immunophenotype, blasts were positive for CD34, CD117, HLA-DR, CD13, CD33, CD15, CD11b, CD19+(dim), cytoCD79a(subset), MPO(subset) and negative for CD14, CD10, CD7, CD8, cCD3, cCD22, and TdT, consistent with Tr-MPAL, B/Myeloid. Ancillary studies revealed normal female karyotype, FLT3-ITD positivity, mutations in RUNX1(frameshift insertion S318fs), SETD2(frameshift insertion P1403fs), WT1(frameshift deletion T377fs), ATM (LI555H), CREBBP (P84S), and DNMT3A (W305). The patient was treated with ALL regimen Hyper-CVAD/methotrexate-cytarabine but relapsed in the post-induction phase with a similar genetics profile. Once remission was achieved, the patient underwent allogeneic SCT and is disease-free while on maintenance therapy post 18 months of initial diagnosis. Conclusion Phenotypically different Tr-MPAL also differ by their underlying genetic abnormalities and may vary in response to therapy. A large cohort of cases may provide us further insights into the genetics and survival outcome of this therapy-related leukemia subtype.

Allogeneic Transplantation to Treat Therapy-Related Myelodysplastic Syndrome and Acute Myelogenous Leukemia in Adults

Patients who develop therapy-related myeloid neoplasm, either myelodysplastic syndrome (t-MDS) or acute myelogenous leukemia (t-AML), have a poor prognosis. An earlier Center for International Blood and Marrow Transplant Research (CIBMTR) analysis of 868 allogeneic hematopoietic cell transplantations (allo-HCTs) performed between 1990 and 2004 showed a 5-year overall survival (OS) and disease-free survival (DFS) of 22% and 21%, respectively. Modern supportive care, graft-versus-host disease prophylaxis, and reduced-intensity conditioning (RIC) regimens have led to improved outcomes. Therefore, the CIBMTR analyzed 1531 allo-HCTs performed in adults with t-MDS (n=759) or t-AML (n=772) between and 2000 and 2014. The median age was 59 years (range, 18 to 74 years) for the patients with t-MDS and 52 years (range, 18 to 77 years) for those with t-AML. Twenty-four percent of patients with t-MDS and 11% of those with t-AML had undergone a previous autologous (auto-) HCT. A myeloablative conditioning (MAC) regimen was used in 49% of patients with t-MDS and 61% of patients with t-AML. Nonrelapse mortality at 5 years was 34% (95% confidence interval [CI], 30% to 37%) for patients with t-MDS and 34% (95% CI, 30% to 37%) for those with t-AML. Relapse rates at 5 years in the 2 groups were 46% (95% CI, 43% to 50%) and 43% (95% CI, 40% to 47%). Five-year OS and DFS were 27% (95% CI, 23% to 31%) and 19% (95% CI, 16% to 23%), respectively, for patients with t-MDS and 25% (95% CI, 22% to 28%) and 23% (95% CI, 20% to 26%), respectively, for those with t-AML. In multivariate analysis, OS and DFS were significantly better in young patients with low-risk t-MDS and those with t-AML undergoing HCT with MAC while in first complete remission, but worse for those with previous auto-HCT, higher-risk cytogenetics or Revised International Prognostic Scoring System score, and a partially matched unrelated donor. Relapse remains the major cause of treatment failure, with little improvement seen over the past 2 decades. These data mandate caution when recommending allo-HCT in these conditions and indicate the need for more effective antineoplastic approaches before and after allo-HCT.

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.

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.

Interleukin-4 and Interleukin-5 Map to Human Chromosome 5 in a Region Encoding Growth Factors and Receptors and Are Deleted in Myeloid Leukemias With a del(5q)

Interleukin-4 (IL-4) is a potent mediator of growth and differentiation of cells of several hematopoietic lineages. Interleukin-5 (IL-5) is a lineage-specific hematopoietic growth factor that stimulates the production of eosinophils and eosinophil colonies from normal human bone marrow cells. By using somatic cell hybrids and in situ chromosomal hybridization, we localized the IL-4 and IL-5 genes to human chromosome 5 at bands q23-31, a chromosomal region that is frequently deleted [del(5q)] in patients with myeloid disorders. By in situ hybridization, the IL-4 and IL-5 genes were found to be deleted in the 5q- chromosome of four patients with refractory anemia (RA) or therapy-related acute nonlymphocytic leukemia (t-ANLL), who had a del(5q). Thus a small segment of chromosome 5 contains IL-4, IL-5, IL-3, and GM-CSF as well as other genes such as CD14 and EGR1. Our findings that each of these genes was deleted in the 5q- chromosome suggest that loss of function of one or more of these genes may play an important role in the pathogenesis of hematologic disorders associated with a del(5q).

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.

Allogeneic Hematopoietic Stem Cell Transplantation in Therapy Related Acute Leukemia.

Therapy related acute leukemia consists of a unique subset of acute leukemia with an increased frequency of high risk cytogenetic and molecular abnormalities, dismal response to therapy, higher relapse rates and poor overall survival. Therapy related acute myeloid leukemia (t-AML) is a better defined disease entity than therapy related acute lymphoid leukemia (t-ALL). However, in recent times, t-ALL is also being increasingly recognized and extensively studied. Therapy related acute myeloid leukemia is usually classified together with therapy related myelodysplastic syndrome. However, the management of these two diseases maybe different regarding needs of induction chemotherapy and eligibility for upfront allogeneic hematopoietic stem cell transplantation (Allo HSCT). There is also evidence regarding differences in prognosis and outcomes between these two entities. Allo HSCT offers a potential for cure in t-AML and t-ALL. However, existing literature on the same is confounded by inclusion of t-MDS and secondary acute leukemias. Here we review the current evidence on the outcomes and predictors of outcomes of Allo HSCT in the management of therapy related acute leukemias. We also shed light into the under-representation of therapy related leukemias in clinical trials. This stresses the need for prospective trials incorporating measurable residual disease monitoring and sequential next generation sequencing based genomic data for accurate prognostication and management of therapy related acute leukemia.

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.