Acute Lymphoblastic Leukemia Treated With Modified Hyper C-VAD Protocol In Iran

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5014-5014
Author(s):  
Hassan Jalaeikho ◽  
Ahmad Ahmadzadeh deylami ◽  
Manoutchehr Keyhani
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Treatment Protocol ◽  
Marrow Transplant ◽  
Intrathecal Methotrexate ◽  
Included Patient ◽  
Induction Regimen ◽  
Enzyme Elevation

Abstract Background Relapse and mortality remains high in Acute Lymphoblastic Leukemia (ALL) with reported 5-year survival less than 39%. Bone marrow transplant (BMT) has been offered to some patients; however, 70% of patients do not have a donor-matched sibling and transplant beds are limited in Iran. We treated a cohort of 251 patients by inducing a remission and then treating with Hyper-CVAD rather than treating with Hyper-CVAD at induction and examined survival compared to reports in the literature. Methods We conducted a retrospective review of survival of 251 treated with a modified protocol of Hyper-CVAD between 2005 and 2012. The treatment protocol used 4-week induction regimen with Vincristine, Daunorubicin, and Dexamethasone. BCR-ABL positive patients also received daily Imatinib. Intrathecal methotrexate and cytarabine were given to patients with brain involvement. Remission was evaluated by a bone marrow biopsy and aspiration. If patient had T-Cell ALL then we add cyclophosphamide to the induction regimen. Hyper-CVAD treatment was initiated two weeks after last dose of Vincristine. Any patient with brain or bone involvement received radiotherapy post induction. BMT was offered to all BCR-ABL positive patients or those who had a suitable donor. All patients in complete remission received monthly vincristine prednisone for 5 days ,6- mercaptopurine every night and methotrexate every week up to 30 months .Patient with persistent liver enzyme elevation received cyclophosphamide instead of methotrexate. Result The mean age was 26 (range 14 to 70). The cohort included patient with T ALL (11%), Burkitt’s type ALL (15%), Pre-B ALL (67%), Pro-B ALL (4%) and BCR-ABL (3%). Sixteen patients died during the first month. Mortality increased to 45 patients at the end of six months. Relapse was the main cause of death. BMT was conducted after complete second remission and suitable patient with BCR-ABL positive patients on 13 occasions but none survived. At 5 years of follow up 129 patients were alive (50.1% survival). Conclusion Our patients experienced an improved survival compared to reports in the literature and many did not have complication of radiotherapy. A modified Hyper-CVAD protocol should be the subject of further investigation for the treatment of ALL. Disclosures: No relevant conflicts of interest to declare.

Successful Engrafment After HLA Identical Granulocyte Transfusion As Support Therapy in a Septic Shock Patient with Acute Lymphoblastic Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4507-4507
Author(s):  
Roberto Ovilla ◽  
Claudia Barrera-Carmona ◽  
Nicolas Guzman-Bouilloud ◽  
Elizabeth Buganza-Torio ◽  
Rosa Jimenez-Alvarado ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Septic Shock ◽  
Acute Lymphoblastic Leukemia ◽  
Bone Marrow Transplant ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Immunosuppressive Treatment ◽  
Marrow Transplant ◽  
Granulocyte Transfusion ◽  
Shock State

Abstract Abstract 4507 A 53 years old male started in February 2010 with ecchymosis, petechiae and spontaneous gum bleeding. He was diagnosed with acute lymphoblastic leukemia, and was started on HYPER-CVAD, in combination with anti-tumoral lysis syndrome measures and antimicrobial, antiviral y antifungal prophylaxis. After finishing HYPER-CVAD phase A, he developed severe myelosuppression even with the use of G-CSF, 72 hours later he presented with abdominal cramping, fever up to 38.2°C and hypotension, with a high clinical suspicion of neutropenic colitis; his mean arterial pressure average was 45 mmHg, he was started on intravenous colloids, dobutamine and norepinephrine drips. Because of severe myelosuppression, septic shock and myocardial depression, a granulocyte transfusion without previous mobilization was performed with an identical sibling donor with concomitant use of granulocytic colony stimulation factor. Severe myelosuppression was maintained during 7 days, however shock state was reversed some hours after performing granulocyte transfusion, without infectious signs, 36 hours later a mononuclear cell infusion was performed from the same donor, with previous 2 days G-CSF mobilization. A gradual increase in leukocyte number appeared, with 400, 900 and finally 1900. A new bone marrow aspiration was performed, where hematopoietic recovery was confirmed from his sister's cells with confirmation by karyotype and microsatellites. He was then considered bone marrow grafted HLA compatible. On April 2010 he presented with acute diarrheic syndrome secondary to a CMV infection, he was started on ganciclovir and intravenous immunoglobulin. On May he presented an Aspergillus pneumonia that was treated both clinically with antifungal therapy and surgically with thoracoscopy to remove the fungi lesion. On October 2010 he started with graft versus host manifestations on the skin and in the liver. He started immunosuppressive treatment with Prednisone and Sirolimus. On November he developed anogenital herpes zoster infection. After this complication, every GVHD manifestation ceded. Now, 28 months post-bone marrow transplant he presents full remission with no evidence of leukemia. Granulocyte transfusion is an uncommon technique. Preferably it should be done with and identical donor. In this case report, the justification of the procedure was to be able to achieve a remission from a potentially irreversible septic shock; this was successfully done, in an unexpected clinical scenario with severe life threatening, and in a casual manner, the patient achieved a successfully bone marrow transplant, and now 30 months post-granulocyte infusion the patient is free from any evidence of disease. Disclosures: No relevant conflicts of interest to declare.

scholarly journals False-positive residual disease assessment after bone marrow transplant in acute lymphoblastic leukemia [letter]

Blood ◽  
1994 ◽  
Vol 84 (4) ◽  
pp. 1352-1353 ◽  
Author(s):  
K Langlands ◽  
NJ Goulden ◽  
CG Steward ◽  
MN Potter ◽  
JM Cornish ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Bone Marrow Transplant ◽  
False Positive ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Marrow Transplant ◽  
Disease Assessment

scholarly journals JAK3 mutants transform hematopoietic cells through JAK1 activation, causing T-cell acute lymphoblastic leukemia in a mouse model

Blood ◽  
2014 ◽  
Vol 124 (20) ◽  
pp. 3092-3100 ◽  
Author(s):  
Sandrine Degryse ◽  
Charles E. de Bock ◽  
Luk Cox ◽  
Sofie Demeyer ◽  
Olga Gielen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Mouse Model ◽  
Lymphoblastic Leukemia ◽  
Marrow Transplant ◽  
Selective Inhibitor ◽  
Mouse Bone Marrow ◽  
Key Points ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Transplant Model

Key Points JAK3 pseudokinase mutants require JAK1 for their transforming potential. JAK3 mutants cause T-ALL in a mouse bone marrow transplant model and respond to tofacitinib, a JAK3-selective inhibitor.

scholarly journals Krüppel-like Factor 4 (KLF4) Suppresses T-Cell Acute Lymphoblastic Leukemia By Inhibiting Expression of MAP2K7 and Expansion of Leukemia Initiating Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3569-3569
Author(s):  
Ye Shen ◽  
Chun Shik Park ◽  
Koramit Suppipat ◽  
Takeshi Yamada ◽  
Toni-Ann Mistretta ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Tumor Suppressor ◽  
Cell Lines ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cells ◽  
Brdu Incorporation ◽  
Jnk Pathway

Abstract Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy in children. Although risk-adaptive therapy, CNS-directed chemotherapy and supportive care have improved the survival of ALL patients, disease relapse is still the leading cause of cancer-related death in children. Therefore, new drugs or novel multi-drug combinations are needed as frontline treatments for high-risk patients and as salvage agents for relapsed disease. T-cell ALL (T-ALL) is a subset of ALL that exhibits activating mutations of NOTCH1 in more than 50% of the patients. However, the use of gamma-secretase inhibitors to reduce NOTCH1 activity has not been successful in patients due to limited response and toxicity. Therefore, identification of genetic factors that cooperate with T-ALL leukemogenesis is needed for the development of alternative therapies. KLF4 is a transcription factor that functions as a tumor suppressor or an oncogene depending on cellular context. Our data showed significant reduction of KLF4 transcripts in lymphoblasts from T-ALL patients compared to blood and bone marrow cells from healthy individuals. In consistent with reduced KLF4 levels, these patients exhibit hyper-methylation of CpG islands located between nt -811 and +1190 relative to KLF4 transcription start site. From these findings we hypothesized that KLF4 has tumor suppressor function in T-ALL leukemogenesis. To test our hypothesis, we transduced 5-FU treated bone marrow (BM) cells from control (Klf4fl/fl), Klf4 null (Klf4fl/fl; Vav-iCre) and Klf4 heterozygous (Klf4fl/+; Vav-iCre) mice with retrovirus carrying a NOTCH1 activating mutant (L1601P-ΔP) and then transplanted these BM cells into irradiated recipient mice. In contrast to controls, mice transplanted with transduced Klf4-null BM cells developed T-ALL with significantly higher penetrance (Klf4 null 76.5% v.s. control 21.3%) and shorter latency (Klf4 null 93 days v.s. control 130 days). Interestingly, Klf4 heterozygous group shows similar survival kinetics as Klf4 null group, suggesting that Klf4 haploinsufficiency is enough to accelerate onset of leukemia. To investigate the effect of Klf4 deletion in established leukemia cells, we transplanted NOTCH1 L1601P-ΔP transduced BM cells from Klf4fl/fl; CreER+ mice to induce leukemia. Post-transplantation deletion of the Klf4 gene by tamoxifen administration was able to accelerate T-ALL development compared to mice injected with vehicle. On the cellular level, loss of KLF4 led to increased proliferation of leukemia cells as assessed by in vivo BrdU incorporation, which correlated with decreased levels of p21 protein. Limited dilution transplantation of primary leukemia cells into secondary recipients showed a 9-fold increase of leukemia initiating cells (LIC) frequency in Klf4null leukemia cells compared to controls, suggesting that KLF4 controls expansion of LIC in T-ALL. To elucidate molecular mechanism underlying KLF4 regulation in T-ALL cells, we performed microarray and ChIP-Seq in control and Klf4 null CD4+CD8+ leukemia cells. Combined analyses revealed 202 genes as KLF4 direct targets, of which 11 genes are also deregulated in human T-ALL cells by comparing with published microarray datasets. One of the top upregulated genes is Map2k7, which encodes a kinase upstream of the JNK pathway. Immunoblots in leukemia cells confirmed increased expression of MAP2K7 protein and enhanced phosphorylation of its downstream targets JNK and ATF2. To further investigate the role of JNK pathway in T-ALL, we tested JNK inhibitor SP600125 in human T-ALL cell lines (KOPTK1, DND41, CCRF-CEM, MOLT3). Interestingly, SP600125 showed dose-dependent cytotoxicity in all human T-ALL cell lines tested regardless of their NOTCH1 status. Overall our results showed for the first time that KLF4 functions as a tumor suppressor in T-ALL by regulating proliferation of leukemia cells and frequency of LIC. Additional study elucidated that KLF4 suppresses the JNK pathway via direct transcriptional regulation of MAP2K7. Moreover, the vulnerability of human T-ALL cell lines to JNK inhibition provides a novel target for future therapy in T-ALL patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Low Epression of MiR-18a Distinguishes Pediatric and Adult Acute Lymphoblastic Leukemia from Each Other

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4991-4991
Author(s):  
Neda Mosakhani ◽  
Mohamed El Missiry ◽  
Emmi Vakkila ◽  
Päivi Heikkilä ◽  
Sakari Knuutila ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Immune Cell ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Tissue Samples ◽  
Inflammatory Microenvironment ◽  
Qrt Pcr ◽  
Response To Chemotherapy ◽  
Pediatric All

Abstract In several adult solid cancers the presence or absence of an inflammatory microenvironment has turned out to be an important prognostic factor. Acute lymphoblastic leukemia (ALL) is seen in both adults and children but the response to chemotherapy and survival is significantly worse in adults than children. Therefore, we wanted to study whether the expression of immune system associated molecular markers would be different in adult and pediatric ALL patients at the time of diagnosis. IDO and FOXP3 were studied from paraffin embedded tissue samples by immunohistochemistry in 12 pediatric and 10 adult bone marrow samples. Inflammation associated miRNA analysis were performed in 19 adult and 79 pediatric ALL patients and involved miR-10, miR-15, miR-16, miR-17-92 cluster, miR-33, miR-146a, miR-150, miR-155, miR-181a, miR-222, miR-223, and miR-339. miRNAs were first analysed by Agilent's miRNA microarray and thereafter validated by qRT-PCR. miRNAs not expressed in at least 75% of one group of samples were excluded. Significance (p <0.05; q<0.1) of differential expression was estimated by t-test for those miRNAs with at least a 2.0 fold change. Sufficient RNA for qRT-PCR was available for 42 pediatric and 19 adult patients. The adult and pediatric ALL patients had quantitatively and qualitatively similar expression of IDO and FOXP3 in leukemic bone marrow samples (p=0.26 and 0.74, respectively). Out of studied miRNAs only miR-18a differed significantly in microarray analysis between adult and pediatric ALL being lower in children (FC -3.74; p 0,0037). Results were confirmed by qRT-PCR (upregulated in adults, FC 3.71, p 0.003161). The other members of the miR-17-92 cluster did not differ significantly. We conclude that pediatric and adult ALL patients have remarkably similar pattern of immune cell associated markers in bone marrow at diagnosis. This is in line with recent evidence that the outcome of the adult ALL patients can be significantly improved if treated with pediatric protocols. However, the low expression of miR-18a in pediatric ALL is interesting and demands further studies. Disclosures No relevant conflicts of interest to declare.

Comparison of Preparative Regimens in Transplants for Children With Acute Lymphoblastic Leukemia

2000 ◽  
Vol 18 (2) ◽  
pp. 340-340 ◽  
Author(s):  
Stella M. Davies ◽  
Norma K. C. Ramsay ◽  
John P. Klein ◽  
Daniel J. Weisdorf ◽  
Brian Bolwell ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Treatment Failure ◽  
Intellectual Development ◽  
Lymphoblastic Leukemia ◽  
Marrow Transplant ◽  
Bone Marrow Transplants ◽  
Free Survival ◽  
Total Body ◽  
Few Data

PURPOSE: Preparative regimens involving total-body irradiation (TBI) produce significant late toxicities in some children who receive bone marrow transplants, including impaired growth and intellectual development. Busulfan is often used as an alternative to TBI, but there are few data regarding its relative efficacy. PATIENTS AND METHODS: We compared outcomes of HLA-identical sibling transplants for acute lymphoblastic leukemia (ALL) in children (< 20 years of age) who received cyclophosphamide plus TBI (CY/TBI) (n = 451) versus those who received busulfan plus cyclophosphamide (Bu/CY) (n = 176) for pretransplant conditioning. Patients received transplants between 1988 and 1995 and their results were reported to the International Bone Marrow Transplant Registry by 144 participating institutions. The CY/TBI and Bu/CY groups did not differ in gender, immune phenotype, leukocyte count at the time of diagnosis, chromosome abnormalities, remission status, or length of initial remission. T-cell depletion was used more frequently in the CY/TBI group; the Bu/CY group included a higher proportion of children who were less than 5 years of age. The median follow-up period was 37 months. RESULTS: The 3-year probabilities of survival were 55% (95% confidence interval [CI], 50% to 60%) with TBI/CY and 40% (95% CI, 32% to 48%) with Bu/CY (univariate P = .003). The 3-year probabilities of leukemia-free survival were 50% (95% CI, 45% to 55%) and 35% (95% CI, 28% to 43%), respectively (univariate P = .005). In a multivariate analysis, the risks of relapse were similar in the two groups (relative risk [RR], 1.30 for Bu/CY v CY/TBI; P = .1). Treatment-related mortality was higher in the Bu/CY group (RR, 1.68; P = .012). Death and treatment failure (relapse or death, inverse of leukemia-free survival) were more frequent in the Bu/CY group (RR, 1.39; P = .017 for death; RR, 1.42; P = .006 for treatment failure). CONCLUSION: These data indicate superior survival with CY/TBI conditioning, compared with Bu/CY conditioning, for HLA-identical sibling bone marrow transplants in children with ALL.

Remarkable donor-derived T cell lymphocytosis before engraftment of a bone marrow transplant for acute lymphoblastic leukemia

2019 ◽  
Vol 61 (1) ◽  
pp. 221-224
Author(s):  
Yurie Nagai ◽  
Shokichi Tsukamoto ◽  
Yutaro Hino ◽  
Yusuke Isshiki ◽  
Miki Yamazaki ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Bone Marrow Transplant ◽  
Lymphoblastic Leukemia ◽  
Marrow Transplant
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