scholarly journals Phase II Study of Hyper-CVAD Plus Nelarabine in Previously Untreated Adult T-Cell Acute Lymphoblastic Leukemia and T-Lymphoblastic Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 177-177 ◽  
Author(s):  
Yasmin Abaza ◽  
Hagop M. Kantarjian ◽  
Elias J. Jabbour ◽  
Deborah A Thomas ◽  
Tapan M. Kadia ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Lymphoblastic Lymphoma ◽  
Mediastinal Disease ◽  
Significant Difference ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Wbc Count ◽  
T Lymphoblastic Lymphoma

Abstract Background: Despite the high complete remission (CR) rates, a significant proportion of adult patients (pts) with T-cell acute lymphoblastic leukemia (T-ALL) and T-lymphoblastic lymphoma (T-LL) treated with standard combination cytotoxic regimens will relapse underscoring the need for better therapeutic strategies. Nelarabine combined with intensive chemotherapy has been shown to be safe and effective in the frontline treatment of pediatric T-ALL. There is limited data on the use of nelarabine in the frontline setting in adult T-ALL and T-LL. Methods: This single-arm phase 2 study was designed to determine the CR rate, overall survival (OS), and safety of adding nelarabine cycles to the standard hyper-CVAD regimen in previously untreated or minimally pretreated (failure to 1 induction course or CR after ≤ 2 cycles) pts with T-ALL and T-LL. Treatment consisted of 8 induction/consolidation cycles of hyper-CVAD (odd courses 1, 3, 5, 7) alternating with high-dose methotrexate (MTX) and cytarabine (Ara-C; even courses 2, 4, 6, 8) followed by 30 months of POMP (monthly vincristine, prednisone, 6-mercaptopurine, and MTX) maintenance therapy. Pts received nelarabine at a dose of 650 mg/m2 IV daily over 2 hrs for 5 days after the 8 cycles of induction/consolidation (Regimen 1). After 30 pts, the protocol was amended to deliver nelarabine after cycles 4 and 5 of induction/consolidation (Regimen 2). All patients also receive nelarabine instead of cycles 6 and 7 of POMP maintenance as early intensification. Late intensification consisted of MTX (100 mg/m2 IV on day 1) plus PEG-asparaginase (2000 IU/m2 IV on day 2) and hyper-CVAD given instead of cycles 18 and 19 of POMP maintenance. CNS prophylaxis consisted of 8 intrathecal treatments of MTX alternating with Ara-C. Pts with initial bulky mediastinal disease or with residual disease after induction were considered for local radiation therapy prior to the start of POMP maintenance. Results: To date, sixty-seven pts have been enrolled; 40 pts (60%) had T-ALL, 26 pts (39%) had T-LL, and 1 pt (1%) had biphenotypic disease. Median age was 37 years (range, 18-78) with 76% (N=51) of the pts males. Performance status was 2 in 9 pts (13%). Four pts (6%) had CNS involvement and 31 pts (46%) had mediastinal disease at diagnosis. Median WBC count at presentation was 8.1 x109/L (range, 0.8-309.2) and 11 pts (16%) had a WBC count > 100 x109/L. Based on immunophenotype, pts were categorized as thymic (N=24), mature (N=8), early T-cell precursor ALL (ETP; N=24), early non-ETP (N=2), and not otherwise specified (N=9). At diagnosis, 41 pts (61%) had diploid cytogenetics, 19 pts (28%) had miscellaneous karyotypic abnormalities, and 7 pts (10%) had indeterminate karyotype due to lack of testing and insufficient metaphases. Eleven pts were in CR at the time of initial presentation after having received 1-2 prior courses of therapy. Overall response rate was 96% (54/56 pts); with 52 pts (93%) achieving CR, 2 pts (4%) PR, and 2 pts (4%) no response. CR rates were similar for T-ALL and T-LL, 87% and 100%, respectively. There were no early deaths within the first month of treatment. With a median follow-up of 35 months (range, 2-98), 44 pts (66%) remain alive of which 41 pts (93%) are in remission. Ten pts (15%) received SCT after achieving CR and remain alive post-SCT; 8 remained in CR and 2 relapsed post-SCT. Nineteen pts relapsed with a median time to relapse of 6.5 months (range, 1.4-62). The site of relapses were: 10 hematologic (BM + blood), 5 extramedullary (EM), 3 BM + EM, and 1 BM + CNS. Twenty-three pts (34%) died including 17 pts with CR dying after relapse. Probability of CR duration at 3 years was 68% (95% CI 54-79 %). The 3-year probability of OS was 65% (95% CI 50-76 %) with a median OS of 82 months. There was no statistically significant difference in OS among the two different nelarabine regimens (Figure 1; p-value=0.93). Grade 3-4 nonhematological toxicity was reported in 60 (90%) pts, most frequent toxicities being infection (82%), elevated alanine aminotransferase (ALT) (16%), and thrombotic events (12%). Conclusion: Hyper-CVAD plus nelarabine is safe and effective in the frontline treatmentof adult T-ALL/T-LL and induces durable remissions. Administration of nelarabine earlier during the course of therapy does not appear to influence the outcome. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Burger:Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Roche: Other: Travel, Accommodations, Expenses; Portola: Consultancy; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Gilead: Research Funding. Wierda:Gilead: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Acerta: Research Funding. Jain:Servier: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Novimmune: Consultancy, Honoraria; Infinity: Research Funding; BMS: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Novartis: Consultancy, Honoraria; Incyte: Research Funding. O'Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Konopleva:Cellectis: Research Funding; Calithera: Research Funding. Daver:Pfizer: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Ariad: Research Funding; Karyopharm: Honoraria, Research Funding; Kiromic: Research Funding; BMS: Research Funding; Sunesis: Consultancy, Research Funding. Thompson:Pharmacyclics: Consultancy, Honoraria. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

scholarly journals Deletion of Pten in CD45-expressing cells leads to development of T-cell lymphoblastic lymphoma but not myeloid malignancies

Blood ◽  
2016 ◽  
Vol 127 (15) ◽  
pp. 1907-1911 ◽  
Author(s):  
Cristina Mirantes ◽  
Maria Alba Dosil ◽  
David Hills ◽  
Jian Yang ◽  
Núria Eritja ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Mouse Model ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Cells ◽  
Hematologic Malignancies ◽  
Lymphoblastic Lymphoma ◽  
Key Points ◽  
Pten Deletion ◽  
Cell Acute Lymphoblastic Leukemia

Key Points CD45-driven expression of Cre generates the first mouse model that allows specific and exclusive deletion of Pten in hematopoietic cells. Pten deletion in CD45-expressing cells causes T-cell acute lymphoblastic leukemia, but no other hematologic malignancies.

Frequency of NUP214-ABL1 Oncogene in Patients with T-Cell Acute Lymphoblastic Leukemia (T-ALL) and Analysis of the Activity of Imatinib and Nilotinib in NUP214-ABL1-Expressing T-ALL Cell Lines.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 710-710
Author(s):  
Alfonso Quintas-Cardama ◽  
Weigang Tong ◽  
Taghi Manshouri ◽  
Jan Cools ◽  
D. Gary Gilliland ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Cell Lines ◽  
Inhibitory Activity ◽  
Lymphoblastic Leukemia ◽  
Fusion Transcript ◽  
Lymphoblastic Lymphoma ◽  
Abl Kinase ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Kinase Inhibitory Activity

Abstract The fusion of ABL1 with BCR results in the hybrid BCR-ABL1 oncogene that encodes the constitutively active Bcr-Abl tyrosine kinase encountered in the majority of patients with chronic myeloid leukemia (CML) and in approximately 30% of pts with B-cell acute lymphoblastic leukemia (B-ALL). Recently, the episomal amplification of ABL1 has been described in 6% of pts with T-ALL (Nat Genet2004;36:1084–9). Molecular analysis demonstrated the oncogenic fusion of ABL1 with the nuclear pore complex protein NUP214 (NUP214-ABL1). We screened 29 pts with T-cell lymphoblastic lymphoma (T-LBL) and T-ALL for the presence of the NUP214-ABL1 fusion transcript by RT-PCR using specific primers for the 5 different transcripts thus far described. Three (10%) pts were found to express this fusion transcript, including 2 with T lymphoblastic lymphoma (NUP214 exon 31) and 1 with T-ALL (NUP214 exon 29). This was confirmed by direct sequencing in all cases. All pts received therapy with hyperCVAD and achieved a complete remission (CR). However, 2 of them died 6 and 9 months into therapy, respectively. One other pt remains in CR (19+ months) by morphologic and flow cytometry criteria. However, NUP214-ABL1 is still detectable in peripheral blood by nested PCR, thus suggesting minimal residual disease (MRD). We then studied the activity of the tyrosine kinase inhibitors imatinib and nilotinib in the NUP214-ABL1-expressing cell lines PEER and BE-13. Although PEER and BE-13 cell viability was reduced with both agents, the IC50 was almost 10-fold higher for imatinib (643 nM) than for nilotinib (68 nM) (F test, p<0.001), which parallels the 10− to 30− fold higher Abl kinase inhibitory activity of nilotinib compared to imatinib in BCR-ABL-expressing cells. Nilotinib also potently inhibited the cell proliferation of BE-13 cells (IC50 131 nM). In contrast, Jurkat cells, a T-ALL cell line which does not carry NUP214-ABL1, were remarkably resistant to both imatinib and nilotinib with an IC50 values greater than 5 μM indicating that the cytotoxicity mediated by both TKIs is not related to a general toxic effect on T-ALL cell lines. The inhibition of cellular proliferation by imatinib and nilotinib was associated with a dose- and time-dependent induction of apoptosis in both PEER and BE-13 cells. In Western blotting, higher inhibition of phospho-Abl and phospho-CRKL (a surrogate of Bcr-Abl kinase status) was observed in PEER cells upon exposure to nilotinib as compared with imatinib at their respective IC50 concentrations for cell growth inhibition. We conclude that NUP214-ABL1 can be detected in 10% of pts with T-cell malignancies and its detection can be used as a sensitive marker of MRD. Imatinib and nilotinib potently inhibits the growth of NUP214-ABL1-expressing cells. Given the higher Abl kinase inhibitory activity of nilotinib with respect to imatinib, this agent must be further investigated in clinical studies targeting patients with T-ALL and T-LBL expressing the NUP214-ABL1 fusion kinase.

scholarly journals Oncogenetic mutations combined with MRD improve outcome prediction in pediatric T-cell acute lymphoblastic leukemia

Blood ◽  
2018 ◽  
Vol 131 (3) ◽  
pp. 289-300 ◽  
Author(s):  
Arnaud Petit ◽  
Amélie Trinquand ◽  
Sylvie Chevret ◽  
Paola Ballerini ◽  
Jean-Michel Cayuela ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Outcome Prediction ◽  
Lymphoblastic Leukemia ◽  
Individual Treatment ◽  
Predictors Of Outcome ◽  
Improve Outcome ◽  
Key Points ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Wbc Count

Key Points In pediatric T-ALL, oncogenetic markers, MRD, and WBC count are independent predictors of outcome. These factors should be used together for individual treatment stratification.

scholarly journals Oncogenetic Risk Classification Based on NOTCH1/FBXW7/RAS/PTEN Mutation Profiles Improves Outcome Prediction in Pediatric T-Cell Acute Lymphoblastic Leukemia, Treated According the Fralle 2000 T Guidelines

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1083-1083 ◽  
Author(s):  
Arnaud Petit ◽  
Amélie Trinquand ◽  
Sylvie Chevret ◽  
Paola Fabiola Ballerini ◽  
Jean-Michel Cayuela ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Low Risk ◽  
Study Cohort ◽  
Risk Patients ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Wbc Count ◽  
Risk Of Relapse

Abstract Background: Risk stratification in childhood T-cell acute lymphoblastic leukemia (T-ALL) is crucial to drive treatment decisions. Since patients with induction failure or relapse are often refractory to further treatment, identifying high risk patients up-front will allow improved treatment. While minimal residual disease (MRD) is the strongest prognosis risk factor used after complete remission (CR), NOTCH1/FBXW7 (N/F) and RAS/PTEN (R/P) mutation profiles at diagnosis have recently been identified to predict outcome in adult T-ALL. Objective: to test whether an oncogenetic classifier using N/F and R/P mutations could improve the detection of children with T-ALL at risk of relapse. Methods: 405 patients with T-ALL aged from 1 to 14 years were treated according to FRALLE T guidelines (FRALLE Study group) between 2000 and 2010. Among them, 220 patients, for whom biological material at diagnosis was available, were tested retrospectively for N/F and R/P mutations. These study cohort patients were representative of overall FRALLE 2000 T-ALLs. CR was achieved in 213 patients. MRD (IgH-TCR markers) tested at CR (day 35) was available for 191 patients. MRD was <10-4 for 114 patients (60%) and ≥10-4 for 77 patients. Patients with N/F mutation and R/P germline (GL) were defined as oncogenetic low risk (LoR), while N/F GL and R/P GL or mutation and N/F mutation and R/P mutation were defined as high risk (HiR). Results: 111 patients were classified as LoR and 109 as HiR. Five-year-CIR and DFS were respectively 35.5% (95% CI, 26.7-44.3) and 59% (95%CI, 50.2-69.6) for HiR versus 13% (95% CI, 6.8-19.2) and 86.8% (80.5-93.5) for the LoR group (Figures A and B). HiR patients were significantly associated with MRD ≥ 10-4 (p=0.0004) and higher risk of relapse (p=0.00002). Among patients with MRD ≥ 10-4, HiR feature worsened the risk of relapse: 5-year-CIR and DFS were respectively 42.8% (95% CI, 28.9-56.7) and 71.1% (95%CI, 56.0-90.2) in HiR versus 28.9% (95% CI, 11.7-46.1) and 50.9% (95%CI, 38.4-67.6) in the LoR group. Among patients with MRD <10-4, 5-year-CIR and DFS were respectively 28.9 % (95% CI, 15.0-42.8) and 71.0% (95%CI, 58.4-86.3) in HiR group versus 4.4% (95% CI, 0-9.2) and 95.5% (95%CI, 90.7-1.00) in LoR group (Figures C and D). As such, the classifier allowed identification of 63% of very low risk patients amongst the MRD<10-4 population. Prognostic values of new oncogenetic risk factors were then analyzed with conventional factors. By univariate analysis, factors identified to predict relapse were male gender (p=0.036), WBC count ≥ 200 G/L (p=0.023), chemoresistance at day 21 (p=0.007), MRD ≥10-4 (p=0.0006) and oncogenetic HiR (p<0.0001). A multivariable cox model including these variables selected the classifier together with WBC count, day 21 chemo-sensitivity and MRD. Based on a stepwise selection procedure, the three most discriminating variables were classifier, WBC count and MRD. The cause specific Hazard Ratio (HR) was 3.22 (95% CI, 1.64-6.28) for oncogenetic HiR versus LoR (p=0.0006), 2.30 (95% CI, 1.26-4.20) for MRD≥10-4 versus MRD<10-4(p=0.0070) and 1.85 (95% CI, 1.01-3.37) for WBC≥200G/L versus <200 G/L (p=0.0456). Based on these three parameters, 8 subsets of patients were defined according to the estimated 5-year CIR. The 58 patients (30%) associating WBC count < 200G/L, classifier LoR and MRD<10-4 were at very low risk of relapse, with a 5-y-CIR of 1.7%. Patients harboring at least one of: WBC count ≥200G/L, classifier HiR or MRD>10-4, demonstrated an increasing CIR, up to 45.8% if all three were associated. Conclusion: in childhood T-ALL, oncogenetic classification using N/F and R/P mutation profiles is an independent predictor of relapse. When combined with MRD and WBC count ≥200 G/L, it significantly improved relapse prediction, particularly amongst the 60% of T-ALLs with MRD <10-4 at day 35. Appropriate integrating these 3 factors, will help optimize treatment. Figure Figure. Disclosures No relevant conflicts of interest to declare.

scholarly journals Clinical Characteristics and Outcomes of Newly Diagnosed Patients with Adult T-Cell Acute Lymphoblastic Leukemia (T-ALL) and T-Lymphoblastic Lymphoma (T-LL) with Hypercvad Based Regimens

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2779-2779
Author(s):  
Preetesh Jain ◽  
Hagop M. Kantarjian ◽  
Farhad Ravandi ◽  
Rashmi Kanagal-Shamanna ◽  
Joseph D Khoury ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Research Funding ◽  
Chromosomal Abnormalities ◽  
Lymphoblastic Leukemia ◽  
Patient Characteristics ◽  
Lymphoblastic Lymphoma ◽  
Survival Outcomes ◽  
Not Otherwise Specified ◽  
T Lymphoblastic Lymphoma

Abstract Introduction: T-cell ALL and T-LL are considered as different spectra of the same neoplastic clone. In various clinical trials of adult ALL, patients with T-ALL and T-LL were combined when analyzing treatment responses and survival outcomes. We have previously reported the results with HCVAD-based regimens in patients with adult ALL. In this study we addressed whether the initial presentation, treatment response, and survival outcomes of adults with T-LL and T-ALL differed when patients were uniformly treated with frontline HCVAD-based regimens at a single institution. Methods: One hundred and fifty previously untreated patients with T-LL (n=54) and T-ALL (n=96) who were treated with HCVAD-based regimens (1992-2016) were included in this analysis. Patient charts were reviewed for initial characteristics, treatment responses including minimal residual disease (MRD) status and survival outcomes; event free (EFS) and overall survival (OS) were analysed. Results: Among 150 patients with previously untreated adult T-ALL/LL, we identified 54 patients (36%) with T-LL and 96 (64 %) with T-ALL. Among patients with available immunophenotype data (n=104), early T precursor (ETP) phenotype was significantly more frequent among patients with T-ALL compared to patients with T-LL (44% vs 19%; p=0.006). The proportion of early, cortical and mature immunophenotype were 2% vs 6%, 31% vs 49% and 16% vs 12% in T-ALL versus T-LL, respectively. The clinical characteristics, response to therapy and outcomes of patients in T-LL versus T-ALL were compared (Table 1 and Figure-1). Patients with T-ALL were slightly older at presentation (median age 37 years [18-67] versus 31 years [17-78]; p=0.07). Patients with T-ALL had significantly higher white blood cell counts, peripheral blood blasts %, bone marrow blasts %, and serum LDH as compared to patients with T-LL. Distribution of chromosomal aberrations was significantly different among the two groups: Diploid karyotype was more commonly encountered in patients with T-LL while patients with T-ALL had more hyperdiploidy and hypodiploidy. Among patients evaluable for response, complete remission (CR) rates were 85% and 95% (p=0.002) in T-LL and T-ALL, respectively. Overall the median follow up times were 72 months (range, 5-243) and 61 months (range, 1-267). Thirty nine (72%) patients with T-LL and 43 (45%) with T-ALL were alive at the time of last follow-up. Patients with T-LL had better outcomes than patients with T-ALL. The 3-year EFS and OS rates were 78% and 74% in patients with T-LLand 53% (p=0.005) and 50% (p=0.001) in patients with T-ALL (Figure 1). Conclusions: In summary, adult patients with T-LL have better outcomes than patient with T-ALL after treatment with HCVAD-based regimens. Additional studies to characterize the genomic profile in tumoral tissues, as well as the pattern of relapses in patients with adult T-LL and T-ALL are ongoing. Table 1 Summary of patient characteristics according to initial diagnosis - T-lymphoblastic lymphoma (T-LL) vs. T-acute lymphoblastic leukemia (T-ALL) *104 patients had full immunophenotype for classification, nos - not otherwise specified, **On available cytogenetic data (47 in T-LL and 82 in T-ALL), of note 3 patients in T-LL and 22 in T-ALL have miscellaneous chromosomal abnormalities Table 1. Summary of patient characteristics according to initial diagnosis - T-lymphoblastic lymphoma (T-LL) vs. T-acute lymphoblastic leukemia (T-ALL). / *104 patients had full immunophenotype for classification, nos - not otherwise specified, **On available cytogenetic data (47 in T-LL and 82 in T-ALL), of note 3 patients in T-LL and 22 in T-ALL have miscellaneous chromosomal abnormalities Disclosures Konopleva: Calithera: Research Funding; Cellectis: Research Funding. Jain:Incyte: Research Funding; Servier: Consultancy, Honoraria; Seattle Genetics: Research Funding; Infinity: Research Funding; Novimmune: Consultancy, Honoraria; Abbvie: Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Genentech: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; BMS: Research Funding. Wierda:Acerta: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Gilead: Research Funding; Genentech: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.

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