Epoetin-alpha compared to standard of care decreases number of packed red blood cell transfusions in patients receiving hyper-CVAD for acute lymphocytic leukemia, lymphoblastic lymphoma, and Burkitt’s lymphoma

7075 Background: Anemia is common in patients with acute lymphocytic leukemia (ALL), lymphoblastic lymphoma (LL), and Burkitt’s lymphoma (BL) treated with chemotherapy and is associated with poor cancer control. Studies have shown that mild correction of anemia is associated with a significant improvement in quality of life. The current standard of care (SOC) for treatment of anemia in ALL, LL, BL is packed red blood cell (PRBC) transfusions. Objectives: To evaluate if EPO 1)decreases number/frequency of transfusions, and 2) adversely influences the complete remission (CR) rate. Methods: Patients with newly diagnosed ALL, LL, or BL receiving hyper-CVAD were randomized to EPO vs SOC within 14 days of starting chemotherapy. EPO dose was 40,000 units SQ weekly and escalated to 60,000 units after 4 weeks if indicated. Both arms received PRBC transfusions as per guidelines. Patients were considered evaluable if they had been on the study for at least 5 weeks. Results: 46 of 70 patients were evaluable: 16 ALL, 4 BL, and 3 LL on EPO (total 23) and 20 ALL, 1 BL, 2 LL in the SOC arm (total 23). The 2 groups were comparable in baseline hemoglobin and number of courses of chemotherapy completed. Median baseline erythroepoietin level was 299 (r 12–10,532) in the EPO arm vs. 104 (r 7–491; p=0.02) in the SOC arm. Time to neutrophil and platelet recovery was comparable in both arms. All patients with ALL (both arms) achieved a CR. One patient with LL on the EPO arm had no response to chemotherapy while all patients with BL and LL on the SOC arm achieved a CR. Conclusions: 1) EPO significantly decreased the frequency and number of PRBC transfusions in patients with ALL, LL, and BL on hyper-CVAD. 2) EPO does not affect recovery of other cell lines. 3) Use of EPO does not appear to have an adverse impact on CR rates in patients with ALL. No significant financial relationships to disclose. [Table: see text]

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Epoetin Alfa vs Standard of Care Decreases Number of Packed Red Blood Cell Transfusions in Patients Receiving Hyper-CVAD for Acute Lymphocytic Leukemia, Lymphoblastic Lymphoma, and Burkitt’s Lymphoma.

Blood ◽

10.1182/blood.v108.11.4477.4477 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4477-4477

Author(s):

Maria E. Cabanillas ◽

Deborah A. Thomas ◽

Hagop Kantarjian ◽

Gloria N. Mattiuzzi ◽

Benjamin N. Bekele ◽

...

Keyword(s):

Blood Cell ◽

Red Blood Cell ◽

Acute Lymphocytic Leukemia ◽

Standard Of Care ◽

Burkitt’S Lymphoma ◽

Lymphoblastic Lymphoma ◽

Lymphocytic Leukemia ◽

Burkitt's Lymphoma ◽

Epoetin Alfa ◽

Red Blood Cell Transfusions

Abstract Background: Anemia is common in patients with acute lymphocytic leukemia (ALL), lymphoblastic lymphoma (LL), and Burkitt’s lymphoma (BL) treated with chemotherapy and is associated with poor cancer control. Studies have shown that even mild correction of anemia has been associated with a significant improvement in quality of life. Although there are studies that show a survival benefit in patients receiving epoetin alfa (EPO), there are at least two randomized trials which reported negative outcomes with respect to progression-free survival in patients with solid tumors treated with EPO. The current standard of care for treatment of anemia in ALL, LL, and BL is packed red blood cell transfusions (PRBC). However, transfusions are time consuming and carry risks of infection and transfusion reaction. Objectives: To evaluate if EPO 1) decreases number and frequency of transfusions, and 2) adversely influences the complete remission (CR) rate to chemotherapy. Methods: Patients with newly diagnosed ALL, LL, or BL receiving hyper-CVAD were randomized to EPO vs standard of care within 14 days of starting chemotherapy. EPO dose was 40,000 units SQ weekly and escalated to 60,000 units after four weeks if indicated. Both arms received blood transfusions as per uniform guidelines. Patients were considered evaluable if they had been on the study for at least five weeks. Results: Forty-six of 70 patients were evaluable and included in this first interim analysis; 23 were treated with EPO. There were 16 ALL, 4 BL, and 3 LL on EPO and 20 ALL, 1 BL, and 2 LL in the standard of care arm. The two groups were comparable in baseline hemoglobin and number of courses of chemotherapy completed. Median age was lower in the EPO arm (32, range 20–71) when compared to the standard of care arm (42, range 16–68; p=0.37). There were more male patients in the EPO arm than standard of care arm (14 vs. 9; p= 0.144). Median baseline erythropoietin level was 299 (range 12–10532) in the EPO arm vs. 104 (range 7–491; p=0.02) in the standard of care arm. The median total number of PRBC units in the EPO group was 12 (range 4–23) compared with 16 (range 9–31) in the standard of care group (p= 0.01). The median number of transfusion events (frequency) was 7 (range 2–13) in the EPO arm compared with 9 (range 4–18) in the standard of care arm (p= 0.03). Time to neutrophil and platelet recovery was comparable in both arms. All patients with ALL had a CR in both arms. On the EPO arm, 1 patient with BL and 1 patient with LL had a partial remission. One patient with LL on the EPO arm had no response to chemotherapy. All patients with BL and LL on the standard of care arm had a CR (p=0.073). Conclusions: In patients with ALL, LL, and BL on hyper-CVAD, EPO decreased the frequency and number of packed red blood cell transfusions. EPO does not affect recovery of other cell lines. Use of EPO in this patient population does not appear to have an adverse impact on CR rates in patients with ALL. The numbers of BL and LL are too small to draw conclusions regarding effect of EPO on response rates.

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Epoetin alfa (EPO) vs standard of care (SOC) decreases number of PRBC transfusions (tx) in patients (pts) receiving hyper-CVAD for acute lymphocytic leukemia (ALL), lymphoblastic lymphoma (LL), and Burkitt’s lymphoma (BL)

Journal of Clinical Oncology ◽

10.1200/jco.2005.23.16_suppl.6703 ◽

2005 ◽

Vol 23 (16_suppl) ◽

pp. 6703-6703 ◽

Cited By ~ 2

Author(s):

G. N. Mattiuzzi ◽

H. Kantarjian ◽

J. Cortes ◽

M. Foudray ◽

B. N. Bekele ◽

...

Keyword(s):

Acute Lymphocytic Leukemia ◽

Standard Of Care ◽

Burkitt’S Lymphoma ◽

Lymphoblastic Lymphoma ◽

Lymphocytic Leukemia ◽

Burkitt's Lymphoma ◽

Epoetin Alfa

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Outcome with Hyper-CVAD/MTX-Ara-C, a Dose-Intensive Regimen, in Acute Lymphocytic Leukemia and Highly Aggressive Lymphoma: A Preliminary Study in a Single Center in China.

Blood ◽

10.1182/blood.v108.11.4529.4529 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4529-4529

Author(s):

Ting Niu ◽

Ting Liu ◽

Bing Xiang ◽

Hong Chang ◽

Yong-qian Jia ◽

...

Keyword(s):

Side Effects ◽

Acute Lymphocytic Leukemia ◽

Burkitt’S Lymphoma ◽

Lymphocytic Leukemia ◽

Burkitt's Lymphoma ◽

Aggressive Lymphoma ◽

Single Center ◽

Cell Disease ◽

Relapsed Disease ◽

Intensive Regimen

Abstract BACKGROUND: Although the safety and efficacy of the Hyper-CVAD/MTX-Ara-C regimen in hematologic malignancies has been well established by the large clinical trials developed at the University of Texas M. D. Anderson Cancer Center, the outcome with this regimen in patients in China has not been determined. The objective of this study was to evaluate the efficacy and potential toxicity of this regimen in acute lymphocytic leukemia (ALL) and highly aggressive non-Hodgkin lymphoma (NHL) in a single center in China. PATIENTS AND METHODS: Between September 2004 and July 2006,36 patients with ALL or highly aggressive lymphoma were treated with the Hyper-CVAD/MTX-Ara-C regimen at our institution. Median age was 35 years (range 14 to 60 years), and 23 patients (64%) were male. All patients are comprised of 19 previously untreated cases and 17 refractory/relapsed ones. Among the 28 patients with ALL, B-cell disease was present in 82%, T-cell disease in 18%, and Ph-positive ALL was present in 18%, refractory/relapsed disease in 46%. Among the 8 patients with highly aggressive NHL, lymphoblastic lymphoma was present in 63%, Burkitt’s lymphoma was in 37% and refractory/relapsed disease in 50%. CNS involvement was present in 8% at diagnosis. Treatment consisted of four cycles of Hyper-CVAD alternating with four cycles of high-dose methotrexate (MTX) and cytarabine therapy, together with intrathecal CNS prophylaxis and aggressive supportive care with granulocyte colony-stimulating factor, transfusion and antibiotic prophylaxis therapy. Maintenance therapy according to cytogenetics and immunophenotype in partial patients included 2 years of treatment with mercaptopurine, MTX, vincristine, and prednisone (POMP). RESULTS: The median follow-up was 7 months (range 1+ to 23+ months). Of the previously untreated 19 patients, seventeen patients (89.47%) achieved complete remission (CR) and no patients died during induction therapy. Of the refractory/relapsed 17 patients, seven cases (41.48%) achieved CR. Remarkably, the CR rate of the patients with Ph-positive ALL was 60.00%(3/5), and Burkitt’s lymphoma 66.67%(2/3). The median finished courses during the dose-intensive phase were 5 (range 1 to 8), and the median time to delivery of all eight courses was 10 months. The estimated 5-year survival and 5-year CR rates were not concluded so far. The incidence of CNS relapse was low (5%). Myelosuppression-associated complications including documented infections, fever of unknown origin, hemorrhage were the more frequent side effects. Other significant side effects included neurotoxicity, renal and hepatic toxicities, fatigue, mucositis, nausea, vomiting, diarrhea, skin rashes, and G-CSF therapy-associated bone aches. CONCLUSION: The preliminary experience from our single center in China demonstrated that Hyper-CVAD/MTX-Ara-C, a dose-intensive regimen with much higher CR is superior to our previous regimens, even in poor-risk Ph-positive ALL, and highly aggressive lymphomas such as lymphoblastic and Burkitt’s lymphoma, and refractory/relapsed ALL/lymphoma. Our data also showed that this regimen is less toxic and well tolerated in patients. Due to the aggressive supportive care, the expense with this regimen is more expensive than conventional chemotherapy. Long-term treatment benefits, such as disease-free survival rates and severe side effects need further investigation in a well-designed, multiple-center study in China with more eligible patients entering onto the study.

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Upregulation of KLF4 Expression in Pediatric B-NHL Lymphomas and Its Association with Low EFS and Poor Survival Following Treatment with Chemotherapy

Blood ◽

10.1182/blood.v118.21.5184.5184 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5184-5184

Author(s):

Mario I Vega ◽

Miriam Hernandez-Atenogenes ◽

Alberto Valencia ◽

Gabriel G Vega ◽

Altagracia Maldonado-Valenzuela ◽

...

Keyword(s):

Transcription Factor ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Burkitt’S Lymphoma ◽

Lymphoblastic Lymphoma ◽

Burkitt's Lymphoma ◽

Large B Cell Lymphoma ◽

Klf4 Expression ◽

Response To Chemotherapy ◽

Large B Cell

Abstract Abstract 5184 Krüppel-like factor 4 (KLF4) is a transcription factor expressed in a variety of tissues in humans and has been implicated in several physiologic processes including development, differentiation, and tissue homeostasis. KLF4 is a bi-functional transcription factor that can either activate or repress transcription depending on the target gene. Human KLF4 is a protein of 470 amino acids with a 55 kDa. It contains three C-terminal C2H2-type zinc fingers that bind DNA. It is divided into three separate domains, namely, an N-terminal activation domain, a central repression domain and a C-terminal DNA-binding domain. For instance, KLF4 acts as a tumor suppressor gene in several cancers (colon, gastric, esophageal, bladder, and NSCLC) or as an oncogene (laryngeal carcinoma, squamous cell carcinoma, ductal carcinoma of the breast). However, the role of KLF4 in hematologic malignancies is still poorly understood. Reported studies in leukemia suggested that KLF4 may be a tumor suppressor. The goal of this study was to investigate the expression and the clinical significance of KLF4 in B-Non-Hodgkin's lymphomas (B-NHLs). Both B-NHL cell lines and patient-derived tumor tissues (TMA) were examined by western blot and immunohistochemistry, respectively. The expression of KLF4 was calculated based on the intensity and the percentage of the area stained, and scoring was corroborated by two pathologists. The complete absence of KLF4 expression was considered as KLF4 negative. Normal peripheral blood mononuclear cells expressed low levels of KLF4, in contrast, there was a significant overexpression of KLF4 in Ramos and Raji (Burkitt's lymphoma) and 2F7 (AIDS lymphoma) B-NHL cell lines. However, the DHL4 (DBLCL) cell line showed similar expression to normal cells. Among the 73 childhood lymphomas studied, 13/23 (57%) of lymphoblastic lymphoma, 7/20 (35%) of large B-cell lymphoma, 4/4 (100%) of anaplastic large cell lymphoma and 5/6 NHL not otherwise specified were KLF4 positive. Noteworthy, 18/18 (100%) Burkitt's lymphoma was KLF4 positive. In addition, the nuclear expression of KLF4 was significantly higher in Burkitt's lymphoma (n=18) compared to the remaining subtypes (lymphoblastic lymphoma, n=23, large B-cell lymphoma n=20 and others). All patients were treated with chemotherapy and the majority of the patients that were KLF4 positive had a stage 3–4 disease. Analysis of the EFS demonstrated that patients' tumors that were KLF4 negative had significantly higher EFS as compared to tumors that were KLF4 positive. Likewise, there was significant prolongation of survival in patients with tumors that were KLF4 negative. We suggest that the expression of KLF4 and poor response to chemotherapy may be attributed to its role in resistance via its regulation by the resistance factor Notch31. In contrast, the absence of KLF4 and good response to chemotherapy may be due to shifting p53 activity from cellular repair to cell death2. The present findings demonstrate that KLF4 may be considered as an oncogene in Burkitt's lymphoma and subsets of other types of lymphoma. The findings also suggest that the expression of KLF4 may be a potential prognostic factor, though, this need to be validated in a large cohort of patients. We propose that KLF4 may be a therapeutic target in patients with B-NHL lymphomas. Disclosures: No relevant conflicts of interest to declare.

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Chromosome abnormalities in 16 finnish patients with Burkitt's lymphoma or l3 acute lymphocytic leukemia

Cancer Genetics and Cytogenetics ◽

10.1016/0165-4608(84)90055-4 ◽

1984 ◽

Vol 13 (2) ◽

pp. 139-151 ◽

Cited By ~ 24

Author(s):

S. Knuutila ◽

E. Elonen ◽

K. Heinonen ◽

G.H. Borgström ◽

T. Lakkala-Paranko ◽

...

Keyword(s):

Acute Lymphocytic Leukemia ◽

Burkitt’S Lymphoma ◽

Chromosome Abnormalities ◽

Lymphocytic Leukemia ◽

Burkitt's Lymphoma

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Outcome with Hyper-CVAD/MTX-Ara-C, a Dose-Intensive Regimen, in Acute Lymphocytic Leukemia and Highly Aggressive Lymphoma in China.

Blood ◽

10.1182/blood.v110.11.4328.4328 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4328-4328

Author(s):

Ting Niu ◽

Ting Liu ◽

Bing Xiang ◽

Hong Chang ◽

Yong-qian Jia ◽

...

Keyword(s):

Side Effects ◽

Acute Lymphocytic Leukemia ◽

Burkitt’S Lymphoma ◽

Lymphocytic Leukemia ◽

Burkitt's Lymphoma ◽

Aggressive Lymphoma ◽

Cell Disease ◽

Long Term Treatment ◽

Relapsed Disease ◽

Intensive Regimen

Abstract Purpose: The objective of this study was to evaluate the efficacy and potential toxicity of the Hyper-CVAD/MTX-Ara-C regimen,a dose-intensive regimen, in the patients with acute lymphocytic leukemia (ALL) and highly aggressive non-Hodgkin lymphoma (NHL) in China. PATIENTS AND METHODS: Between June 2004 and June 2007, fifty-six patients with ALL or highly aggressive lymphoma were treated with the Hyper-CVAD/MTX-Ara-C regimen at our institution. Median age was 26 years (range 13 to 60 years), and 35 patients (62.50%) were male. All patients were comprised of 32 previously untreated cases and 24 refractory/relapsed ones. Among the 41 patients with ALL, B-cell disease was present in 82.93%, T-cell disease in 17.07%, and Ph-positive ALL was present in 14.63%, refractory/relapsed disease in 43.90%. Among the 15 patients with highly aggressive NHL, lymphoblastic lymphoma was present in 46.67%, Burkitt’s lymphoma was in 53.33% and refractory/relapsed disease in 40.00%. CNS involvement was present in 8% at diagnosis. Treatment consisted of four cycles of Hyper-CVAD alternating with four cycles of high-dose methotrexate (MTX) and cytarabine therapy, together with intrathecal CNS prophylaxis and aggressive supportive care with granulocyte colony-stimulating factor (G-CSF), transfusion and antibiotic prophylaxis therapy. Maintenance therapy based on cytogenetics and immunophenotypes in most of patients contained 2-year treatment with mercaptopurine, MTX, vincristine, and prednisone (POMP). RESULTS: The median follow-up time was 7 months (range 1+ to 37+ months). Of the previously untreated 31 patients, twenty-nine patients (93.55%) achieved complete remission (CR) and no patients died during induction therapy. Of the refractory /relapsed 24 patients, fourteen cases (58.33%) achieved CR. Remarkably, the CR rate of the patients with Burkitt’s lymphoma was 75.00% (6/8). The median courses finished during the dose-intensive phase were 4 (range 1 to 8), and the median time to delivery of all eight courses was 10 months. The estimated 3-year overall survival (OS) for the untreated and refractory/relapsed patients with ALL was 46.80% and 28.60%, respectively. Meanwhile, the estimated 2-year OS for the aggressive NHL patients was 84.00%. Compared with the patients with ALL who did not receive CR and get less than four courses of this regimen, the patients who did receive CR and get more than four courses of this dose-intensive regimen showed much better OS (p<0.05). The incidence of CNS relapse was low (5%). Myelosuppression-associated complications including documented infections, fever of unknown origin, hemorrhage were the more frequent side effects. Other significant side effects included neurotoxicity, renal and hepatic toxicities, fatigue, mucositis, nausea, vomiting, diarrhea, skin rashes, and G-CSF therapy-associated bone aches. CONCLUSION: The present outcome from our single center in China demonstrated that Hyper-CVAD/MTX-Ara-C, a dose-intensive regimen with much higher CR was superior to our previous regimens, even in patients with highly aggressive lymphoma such as lymphoblastic and Burkitt’s lymphoma, and in refractory/relapsed ALL/lymphoma ones. Our study also showed that this regimen was less toxic and well tolerated in most of treated patients in China. Long-term treatment benefits and severe side effects needed further investigation in a well-designed, multiple-center study in China with more eligible patients entering onto the study.

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