scholarly journals Ripk3 Signaling Regulates Hematopoietic Stem Cell Number and Function during Stress

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3714-3714
Author(s):  
Lei Zhang ◽  
Huacheng Luo ◽  
Jing Li ◽  
Hong-Min Ni ◽  
Mark Sellin ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Low Dose ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Low Doses ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Leukemia Development ◽  
Serial Transplantation

Background: Among all tissues, bone marrow (BM) is the most sensitive tissue to ionizing radiation (IR)-induced acute tissue damage (ATD) and chronic long-term residual damage (LT-RD). BM failure and a significant reduction in blood cells (pancytopenia) often occurs within days after exposure to IR due to the massive death of proliferative hematopoietic progenitor cells (HPCs). However, due to their quiescent cell cycle status and reduced fidelity of DNA repair feature, many hematopoietic stem cells (HSCs) cannot fully eliminate such damage and enter senescence; this results in LT-RD. Abnormal dysplastic hematopoiesis is the most common LT-RD in most victims of IR, followed by an increased risk of leukemia/lymphoma development. Thus IR exposure is an established cause of BM failure and leukemia. A significant increase in the production of inflammatory cytokines is induced by IR which contributes to the pathogenesis of both ATD and LT-RD. Such inflammatory cytokines induce the activation of Ripk3-Mlkl-mediated necroptotic signaling in HSCs. However, the role of Ripk3-Mlkl signaling in IR-induced damage has not studied. Experimental procedures: The self-renewal capacity of HSCs among Ripk3-/-, Mlkl-/- and WT mice were examined and compared by serial transplantation assay. The phenotypes of ATD and LT-RD induced by different dosages of IR were compared among Ripk3-/-, Mlkl-/- and WT mice. The mechanism by which Ripk3 signaling prevents IR-induced leukemia development was studied. Results: Ripk3-Mlkl signaling is not required for hematopoiesis during homeostatic condition. However, during serial transplantation, inactivation of such signaling prevents stress-induced loss of HSCs. Interestingly, Ripk3 signaling also induces an Mlkl-independent ROS-p38-p16-mediated senescence in HSCs. Thus Ripk3-/- HSCs showed better competitive hematopoietic ability compared to Mlkl-/- and WT HSCs during serial transplantation. A sub-lethal dosage of IR (6Gy) induces Ripk3-dependent NF-κB activation and pro-survival gene expression in HSCs, which is necessary for the survival of damaged HSCs. After 6Gy IR, although DNA damage is repaired in most HSCs within 2 days, a proportion of HSCs in WT and Mlkl-/- mice fail to fully repair the damage and undergo p53-p21-dependent senescence. However such cells in Ripk3-/- mice die from apoptosis. Thus the remaining HSCs in Ripk3-/- mice should be functionally normal, while a proportion of the remaining HSCs in Mlkl-/- and WT mice remain damaged but senescent, all as demonstrated by competitive hematopoietic reconstitution assay. Multiple low-doses of IR (1.75Gy once week × 4) induce HSC exhaustion in WT mice but not in Ripk3-/- and Mlkl-/- mice. Interestingly, almost all Ripk3-/- mice develop acute lymphoblastic leukemia within 200 days after such low dose IR, while 45% of WT and 60% of Mlkl-/- mice develop thymomas within 360 days (see Figure). Mechanistically, such low-dose IR stimulates chronic inflammatory cytokine production. Such cytokines induce Ripk3-Mlkl-mediated necroptosis in response to HSC exhaustion observed in WT mice. These cytokines also induce Ripk3-ROS-p38-p16-mediated senescence in response to impaired HSC functioning observed in both WT and Mlkl-/- mice. In Ripk3-/- mice, due to the lack of both necroptotic and senescent signaling, mutant HSCs accumulate and leukemia development is accelerated. Conclusion: Ripk3 signaling plays distinct roles in HSCs in response to different doses of IR. High-dose IR induces Ripk3-dependent NF-κB/survival signaling, which is required for the survival of HSCs which fail to repair the damage. Thus temporal inhibition of Ripk3-NF-κB signaling might help to remove the damaged HSCs thus preventing the occurrence of LT-RD. However multiple low-doses of IR induces Ripk3 activation in HSCs which represses leukemia development by inducing both ROS-p38-p16-mediated senescence and Ripk3-Mlkl-mediated necroptosis. Induced activation of Mlkl-necroptosis might help to repress leukemia development by removing damaged HSCs. Disclosures No relevant conflicts of interest to declare.

Combined Analysis of Treatments for Pediatric T-ALL in KYCCSG Protocols, ALL-96 and ALL-02.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4102-4102
Author(s):  
Yasuhiro Okamoto ◽  
Yoshihisa Nagatoshi ◽  
Akinobu Matsuzaki ◽  
Aiko Suminoe ◽  
Hideki Nakayama ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Chromosomal Abnormalities ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Cranial Irradiation ◽  
High Dose ◽  
Costal Margin ◽  
Hematopoietic Stem ◽  
Combined Analysis

Abstract Abstract 4102 Background Previously we reported the result of Kyushu-Yamaguchi Children's Cancer Study Group (KYCCSG) protocol, ALL-96, for pediatric acute lymphoblastic leukemia (ALL) (ASH meeting in 2005). The 7-year event-free survival (EFS) and overall survival (OS) rates were 72% (95% CI; 68 - 76 %) and 85 % (95% CI; 80 - 90 %), respectively. Following protocol, ALL-02, was aimed to assess the usefulness of polymerase chain reaction (PCR)-based minimal residual disease (MRD) in the same context as ALL-96 protocol. Purpose In this combined analysis, we analyzed the outcome and risk factors for relapse/survival in children with T-ALL who were treated with the ALL-96/ALL-02 protocols. Study Design and Treatment A total of 42 patients (22 of 218 in ALL-96 and 20 of 165 in ALL-02, 26 males and 16 females) with median age of 8 years (range 1 - 14) were treated. Patients were classified into 2 groups, standard risk (SR) and high risk (HR). HR patients had one of the followings: high white blood cell (WBC) counts more than 50,000/μl, T-cell immunophenotype, central nervous system (CNS) disease at diagnosis, organomegaly (hepatomegaly or splenomegaly more than 5 cm below costal margin), M2/3 marrow at day 15 of induction therapy. Both protocols consisted of induction, early intensification, consolidation, late intensification and maintenance therapy. Predonisolone (PSL), weekly vincristine (VCR), 4 doses of daunorubicin (DNR), 8 doses of L-asparaginase (L-asp) and 2 or 4 doses of intrathecal (IT) methotrexate (MTX) depending on the CNS status, were given during induction. In early intensification, DNR, cytarabine (CA), etoposide and 6-mercaptopurine (6-MP) were given. Consolidation consisted of intermediate dose of MTX, combination of cyclophosphamide(CPM), CA and 6-MP, and high dose CA. Late intensification similar to induction included 2 weeks of dexamethasone (DEX), weekly VCR, 2 doses of pirarubicin, single dose of CPM, 5 doses of L-asp and IT-MTX followed by combination of CA, 6-MP, IT-MTX along with 18 Gy cranial irradiation in 12 fractions. In ALL-96 protocol, patients were randomized to receive maintenance therapy of either combination of 6-MP/MTX and DEX/ VCR pulse (A-arm) or LSA2L2-type therapy (B-arm). In ALL-02 protocol, A-arm was chosen as a maintenance therapy based on result of ALL-96. No patient underwent hematopoietic stem cell transplantation (SCT) in 1st complete remission (CR). Results Median follow-up periods were 96 and 38 months in ALL-96 and ALL-02, respectively. Two patients were off-protocol before achieving CR because of toxicity and chromosome abnormality with t(4;11). Induction rate in 40 patients was 95%. All 14 events were relapses and TRM rate was 0%. Last event occurred at 40 months. The sites of relapse were isolated BM in 9, isolated testis in 2, isolated CNS in 1 and combined sites in 2. Nine died from disease progression and 2 died from toxicity after SCT in 2nd CR. The 4-year EFS and OS rates in all patients were 55 % (95 % CI; 39 – 71 %) and 71 % (95 % CI; 56 -86 %), respectively. EFS of ALL-96 and ALL-02 were 50 %[95 % CI; 29 -71 %]) and 65 % [95 % CI; 45 - 85 %]), respectively. OS of ALL-96 and ALL-02 were 59 % [95 % CI; 39 – 80 %]) and 90 % [95 % CI; 77 - 103 %]), respectively (p = 0.063). EFS of patients treated in A and B arm were 60 % [95 % CI; 41 -71 %]) and 55 % [95 % CI; 25 - 84 %]), respectively. None of age, sex, organomagaly, WBC, chromosomal abnormalities, CNS status, protocol, and maintenance arm was identified as a risk factor for relapse or survival. Two of 10 (ALL-96) and 3 of 4 (ALL-02) relapsed patients have survived with allogeneic SCT. Conclusion Although T-ALL patients received an intensified treatment including cranial radiation, the outcome was unsatisfactory. One possible explanation for better OS in ALL-02 protocol is that the majority of relapsed patients in ALL-02 were salvaged by SCT in 2nd CR. Disclosures: No relevant conflicts of interest to declare.

A Brief Use of Imatinib Immediately Before Hematopoietic Stem Cell Transplantation (HSCT) in Children with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL). Results of the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) Study Ph+ALL04

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2554-2554
Author(s):  
Atsushi Manabe ◽  
Hirohide Kawasaki ◽  
Motoaki Chin ◽  
Atsushi Sato ◽  
Kimikazu Matsumoto ◽  
...  
Keyword(s):  
Survival Rate ◽  
Medical Information ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Cord Blood Transplantation ◽  
High Dose ◽  
Induction Phase ◽  
Study Group ◽  
Pediatric Leukemia ◽  
Hematopoietic Stem

Abstract Abstract 2554 Aims: Children with Ph+ALL generally have a poor prognosis when treated with chemotherapy alone. The timing and duration of the use of imatinib has not been determined. We investigated a role of imatinib immediately before HSCT. Methods: All the patients with ALL were screened for diagnosis of Ph+ALL using RT-PCR. Children with Ph+ALL were enrolled on JPLSG Ph+ALL04 Study within 1 week of initiation of treatment for ALL. Treatment regimen consisted of 5 therapeutic phases: Induction phase (5-drug induction), Intensification phase (high-dose cytarabine and BFM Ib), Re-induction phase (4-drug re-induction), 2 weeks of Imatinib monotherapy phase (23 weeks after diagnosis), and HSCT phase (Etoposide+CY+TBI conditioning). Before and after each phase, minimal residual disease (MRD), the amount of BCR-ABL transcripts, was measured with the real-time PCR method (cut-off 50 copies/microgram RNA). The study was registered in UMIN-CTR (Medical Information, University hospital Medical Information Network - Clinical Trials Registry): UMIN ID C000000290. Results: During the period 2004–08, 42 patients were registered in the Ph+ALL04 study. Out of 42 patients, 37 patients (88%) achieved CR and 7 of 37 patients also achieved MRD-negative after induction phase. There were 13 patients who had no MRD at the beginning of imatinib monotherapy phase, and 14 patients were MRD-negative after imatinib phase, consequently, 14 patients were MRD-negative at the time of HSCT. Six patients relapsed before HSCT. In total, 31 patients received HSCT in 1st CR. All the patients had engraftment and no patients died because of complications of HSCT. Five patients relapsed after HSCT and 4 of the 5 patients were MRD-negative before HSCT and the other patient had detectable MRD although it was less than 50 copies. Twenty-six patients continue to be in 1st CR and MRD-negative for median of 3 years after diagnosis. The 3-year event-free survival rate and over-all survival rate for all the patients was 57% and 80%, respectively (figure 1). Five patients did not achieve CR after induction phase and they were treated with imatinib-contained chemotherapy. Four of the 5 patients achieved CR. All of the 4 patients received cord blood transplantation and remains in continued CR. Interpretation: The chemotherapy we employed was based on the previous high-risk regimen of TCCSG (Tokyo Children's Cancer Study Group) L-99-15 Study. The chemotherapy was intensive enough to induce MRD-negative in 13 at the time of imatinib phase and 31 of 42 patients were in CR at the time of HSCT (around 25–28 weeks after diagnosis). We planned to assess the efficacy of imatinib immediately before HSCT but it was not possible because of the low amount of MRD in most patients at the beginning of imatinib phase. Conclusion: Although EFS and OS was excellent in this study, 88% of induction rate appeared unsatisfactory and relapse occurred before HSCT in 6 out of 37 patients who achieved CR after induction phase. Earlier and longer use of imatinib may improve EFS in children with Ph+ALL and HSCT may be omitted in a subset of patients who achieve an early and deep remission status. Disclosures: No relevant conflicts of interest to declare.

Sorafenib Is Contributing to Salvage Chemotherapy and Is Effective Given Alone for Maintenance in AML FLT3 ITD Patients Relapsing Post Allo Hematopoietic Stem Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5265-5265 ◽  
Author(s):  
Emilia Jaskula ◽  
Janusz Lange ◽  
Mariola Sedzimirska ◽  
Andrzej Lange
Keyword(s):  
Maintenance Therapy ◽  
Low Dose ◽  
Liver Toxicity ◽  
Conflicts Of Interest ◽  
Normal Karyotype ◽  
Salvage Chemotherapy ◽  
Remission Induction ◽  
Comparative Genomic ◽  
High Dose ◽  
Hematopoietic Stem

Abstract Normal karyotype AML patients with FLT3 ITD have a higher risk of relapse than those lacking this mutation (Estey EH, Am J Hematol. 2013). Our comparative genomic hybridization study (77 patients) showed that AML cases with as compared to those without FLT3 ITD had significantly lower number of amplifications or deletions (number of total CNV aberrations: 18±4 vs 51±8, p=0.003). The latter observation in concert with that of others (Thiede, Blood 2002) suggest that FLT3 ITD mutation if present in normal karyotype patients is a key player in the pathogenesis of leukaemia and targeting this mutation may be used successfully in FLT3 ITD positive patients relapsing post HSCT. This was also the case in the two patients presented in this study. Patient UPN 952, male, 53 years old, AML M4 (FAB), normal karyotype, received alloHSCT in 2 CR after completion of two lines of remission induction therapies (first: DA3+7 (Daunorubicin, Ara-C), HAM, high dose Ara-C; second: ICE (IDA, Ara-C, VP-16)) and then promptly transplanted. He relapsed 56 days after transplantation. Patient UPN 938, female, 50 years old, AML, normal karyotype, received as an induction DA 3+7, and for consolidation HAM and high dose Ara-C and completed only one course of the maintenance therapy and transplanted in CR. Both cases were transplanted from unrelated donors (10/10 HLA A, B, C, DR and DQ alleles matched), they received myeloablative conditioning (i.v. Busulfan and Cyclophosphamide) and Cyclosporin A as GvHD prophylaxis. At relapse they received salvage chemotherapy tailored to their biological performance (UPN 938 having Age Adjusted Charlson Comorbidity Index 3 received FLAG and UPN 952 with the index 9, ECOG 3, DA2+5). Both cases received in addition Sorafenib (two times 400 mg per day). The response was prompt and the marrow was free from blasts beginning from 11 day post chemotherapy. UPN 952 received as a maintenance only one course of 6-TG with low dose of Ara-C. Due to the substantial comorbidity and liver toxicity WHO3 further chemotherapy treatment was terminated. The patient was left only on Sorafenib (2 times 200 mg per day). UPN 938 was receiving the maintenance therapy (AML protocol) in 6 – 8 weeks intervals based on low dose Ara-C with 6TG or DNR and also Sorafenib (2 times 200 mg per day). In both cases FLT3 signalling pathway (FLT3 Pathway Mutation PCR Array, SABiosciences, Qiagen) revealed a lack of any additional mutation at the check points in FLT3, KRAS, HRAS, NRAS, MEK1, PIK3CA, BRAF and PTEN genes. UPN 938 had in addition to FLT3 ITD mutation c.1807_1808insATGAATATGATCTCAAAT (p.K602_W603insYEYDLK) insertion which relevance was not so far describe. Sorafenib resistance mutations were not found. The patients were on Sorafenib for 8 (UPN 938) and 9 months (UPN 952). The course of UPN938 was uncomplicated. The second case showed mild aGvHD symptoms evolving into cGvHD (skin lesions and dry eye) slowed down with rapamicine. Up to now the patients are in CR and free from FLT3 ITD. The main observation points: - Sorafenib with chemotherapy tailored to the biologic performance of patients contributes to the efficient salvage in patients with relapsing FLT3 ITD positive AML post HSCT and is also effective given alone as a maintenance. - Side effects were seen in one out of two patients likely associated with the blocking of VEGFR signalling transmission (hand foot skin rash, von Willebrandt factor activity – 388%). Conclusion: The use of multikinase inhibitor (Sorafenib) contributes effectively to salvage therapy in FLT3+ AML patients relapsing post alloHSCTSorafenib given alone is able to maintain long-lasting remissionSide effects are individually dependent Supported by NBiR CellsTherpy grant and Byer Health Care Disclosures No relevant conflicts of interest to declare.

scholarly journals FoxM1 Haploinsufficiency Drives Clonal Hematopoiesis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 726-726
Author(s):  
Chunjie Yu ◽  
Yue Sheng ◽  
Zhijian Qian
Keyword(s):  
Cell Cycle ◽  
Progenitor Cells ◽  
Low Dose ◽  
Conflicts Of Interest ◽  
Clonal Expansion ◽  
Brdu Incorporation ◽  
Quiescent State ◽  
Dapi Staining ◽  
Hematopoietic Stem ◽  
Increased Risk

Hematopoiesis is an orchestrated process in which hematopoietic stem cells (HSCs) can self-renew and produce all lineages of blood cells. Majority of HSCs are in a quiescent state with a low growth rate. However, some genetic mutations that occur in HSCs impel HSCs to exit the quiescent state and to proliferate excessively, which enables mutant HSCs to outcompete normal HSCs and leads to clonal expansion of mutant HSCs. Myelodysplastic syndromes (MDSs) as a clonal disease, arise from the expansion of mutant HSCs and are characterized by morphologic dysplasia, ineffective hematopoiesis and an increased risk of transformation to acute myeloid leukemia. FoxM1 is one of transcription factors in the family of Fox ('Forkhead box') proteins. Analysis of public database revealed that the expression level of FOXM1 was decreased significantly in CD34 + cells from a subset of patients with MDS as compared to healthy individuals. Thus, we sought to determine whether haploinsufficiency of FOXM1 contributes to the development of MDS in mice. Our study showed that haploinsufficiency of Foxm1 led to an expansion of hematopoietic stem/progenitor cells in mice. Since FoxM1 has previously been implicated in regulation of cell cycle, we determined the cell cycle status of Foxm1 heterozygous HSCs. By BrdU incorporation assay, we showed that Foxm1 heterozygous HSCs have an increased S phase and G2/M phase as compared to control HSCs from wildtype mice. Additional analysis with Hochest33342/Pyronin-Y staining and Ki67/DAPI staining showed a significant decrease in the number of quiescent (G0) cells in Foxm1 heterozygous HSCs as compared to control HSCs. These results suggest that FoxM1 haploinsufficiency promotes HSCs to exit quiescence and to enter cell cycle, thereby leading to exhaustion of HSCs. To further assess the function of Foxm1 heterozygous HSCs in vivo, we performed competitive repopulation assay. We found that Foxm1 haploinsufficiency HSCs exhibited competitive repopulation advantage in the first and secondary recipient mice, but displayed significantly decreased capacity of repopulation in tertiary recipient mice as compared to control HSCs, suggesting that Foxm1 haploinsufficiency promoted clonal expansion of HSCs, which leads to an exhaustion of HSCs eventually. HSC proliferation can be induced by some specific immune effectors such as Toll-like receptor 4 (TLR4). Lipopolysaccharide (LPS) stimulates HSC proliferation by activating TLR4 signaling pathway. Low dose of LPS treatment over time accelerated the development of MDS in mice. Interestingly, low dose of LPS injection chronically induced defects in hematopoiesis in Foxm1 haploinsufficient mice but not the control wildtype mice. Recipient mice transplanted with Foxm1 heterozygous BM cells but not the control BM cells developed MDS-like disease with cytopenia and a decreased number of hematopoietic stem/progenitor cells after LPS stimulation. Moreover, we found that nearly half of aged Foxm1 haploinsufficient mice (20 months) developed splenomegaly. Analysis of histologic sections in Foxm1 haploinsufficient mice showed that the mice developed hematopoietic dysplasia including dysplastic megakaryocytes with bizarre-shaped nuclei in bone marrow and extramedullary hematopoiesis with accumulation of myeloid cells in spleen. RNA-seq analysis indicated that haploinsufficiency of Foxm1 perturbed multiple stem cell-maintenance mechanisms especially in metabolic processes. Taken together, our studies suggest that Foxm1 haploinsufficiency in mice causes clonal expansion of HSCs and promotes MDS-like disease, which underscores the significant role of FOXM1 downregulation in the initiation and development of human MDS. Disclosures No relevant conflicts of interest to declare.

Clofarabine-Containing Chemotherapy Does Not Increase the Risk of Infectious Complications in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4256-4256
Author(s):  
Michael S Mathisen ◽  
Hagop M Kantarjian ◽  
Elias Jabbour ◽  
Guillermo Garcia-Manero ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Viral Infections ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Demographic Data ◽  
Neutropenic Fever ◽  
Chemotherapy Cycle ◽  
Cancer Center ◽  
High Dose ◽  
Cell Transplant ◽  
Increased Risk

Abstract Abstract 4256 Background: Clofarabine is a purine nucleoside analog currently approved for relapsed pediatric acute lymphoblastic leukemia (ALL). Its role is also being investigated in various other hematologic malignancies, including AML. While desirably myelosuppressive, clofarabine is also lymphotoxic, which may impair cellular mediated immunity and result in higher rates of severe and/or atypical infections. Recently, an analysis of patients receiving clofarabine as salvage therapy for AML revealed a potentially increased risk for “unconventional” infections (Knoebel RW, Leuk Res, 2011). At the M.D. Anderson Cancer Center (MDACC), clofarabine has been tested as a component of multi-agent therapy for the frontline treatment of younger patients with AML. We hypothesized that clofarabine may increase the infectious burden placed on these patients. Methods: We conducted a retrospective comparison of patients receiving clofarabine containing chemotherapy (CIA: clofarabine 20 mg/m2 IV daily for 5 days, idarubicin 10 mg/m2 IV daily for 3 days, cytarabine 1,000 mg/m2 IV daily for 5 days) versus non-clofarabine containing chemotherapy (IA: idarubicin 12 mg/m2 IV daily for 3 days, cytarabine 1,500 mg/m2 IV continuous infusion over 24 hours for 4 days) from 2007 – 2011. Consolidation cycles contained the same agents given according to an attenuated schedule. Variables extracted from the medical record included demographic data, number of cycles per patient, achievement of complete remission (CR), application of allogeneic stem cell transplant (allo-SCT), episodes of neutropenic fever, diagnosis of pneumonia, and diagnosis of atypical infections. Atypical infections were defined as viral infections, Pneumocystis Jirovecii, Nocardia, mycobacterial infections, Listeria, Legionella, Mucormycosis, or radiographic evidence of an atypical infection (REAI). Patients were followed until relapse, allo-SCT, or 6 months after the previous chemotherapy cycle. Results: 49 patients per group followed predominantly at MDACC throughout the duration of therapy were analyzed. Prophylactic antimicrobials prescribed after each chemotherapy cycle generally included valacyclovir, voriconazole, and an oral fluoroquinolone for all patients. The groups were well balanced in terms of age, therapy duration (2.7 cycles per patient on CIA versus 2.6 cycles per patient on IA), CR rate (CIA 73%, IA 71%), and predisposition to allo-SCT (CIA 49%, IA 45%). In the CIA group, 13 patients were diagnosed with pneumonia versus 15 patients in the IA group. Episodes of neutropenic fever per cycle also did not appear to differ between the groups (CIA 0.5, IA 0.62). Regarding atypical infections, there were 3 in the CIA cohort (1 Mucor, 2 REAI) versus 9 in the IA cohort (1 Mucor, 2 RSV, 6 REAI). Conclusions: Patients with AML treated in the frontline setting with clofarabine-containing chemotherapy do not appear to be subjected to an increased infectious risk compared with other high-dose ara-C-containing chemotherapy. In addition, we did not observe a higher rate of atypical infections in the group treated with the CIA regimen. We further plan to evaluate our older population of patients as well as those patients who receive clofarabine in the relapsed setting. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT) for Children and Young Adults with T-Cell Acute Lymphoblastic Leukemia (T-ALL) Treated at Investigator Discretion: A Report from Children's Oncology Group (COG) AALL0434

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 659-659
Author(s):  
Stuart S. Winter ◽  
Meenakshi Devidas ◽  
Brent Wood ◽  
Zhiguo Chen ◽  
Natia Esiashvili ◽  
...  
Keyword(s):  
Young Adults ◽  
Multivariate Analyses ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Hazard Ratio ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Leucovorin Rescue ◽  
Children And Young Adults ◽  
To Receive

Abstract Introduction: Salvage therapies in children and young adults with relapsed T-ALL are successful in <10% of patients, thus relapse prevention is a first priority. Contemporary strategies have included the use of intensified multi-agent regimens, novel therapies, and alloHSCT. COG AALL0434 did not include an alloHSCT treatment arm. To mitigate the risk of relapse, some patients were taken off study and, at investigator discretion, referred for alloHSCT. We retrospectively collected data to identify which patients were taken off study, either during induction, or after end-induction risk assignment to receive alloHSCT, for reasons other than relapse. In particular, it was unknown how alloHSCT affected the outcomes for patients with specific subsets of disease, such as induction failure (IF) or with the early thymic precursor (ETP) phenotype. Patients and Methods: From 2007-2014, AALL0434 enrolled 1,895 patients (1,596 T-ALL) and included a 2 x 2 pseudo-factorial randomization using a COG-modified BFM regimen. Patients were randomized to receive escalating dose methotrexate without leucovorin rescue plus pegaspargase (CMTX) or High Dose MTX (HDMTX) with leucovorin rescue in a single Interim Maintenance phase, with or without six 5-day courses of nelarabine. No patients were risk stratified on the basis of ETP. Participants with ≥ 25% marrow blasts on day 29 of induction (IF) were assigned to receive HDMTX with nelarabine. All patients with intermediate risk (IR), high risk (HR) or IF received cranial irradiation. Results: Among 1385 eligible, evaluable T-ALL patients for whom survey information was available, 333 (24%) were taken off therapy during induction prior to randomization. Thirty-two (9.6%) of these 333 subsequently underwent alloHSCT (19 with M1, 9 with M2 and 4 with unknown Day 29 marrow status). At the end of induction, 1052 patients were risk stratified and consented to randomization. Of these, 43 patients (4.3%) were subsequently taken off protocol therapy for alloHSCT [0 low risk (LR), 2 IR, 21 HR and 20 IF]. For the 75 patients who were taken off protocol therapy during or after induction and underwent alloHSCT, time to transplantation from end induction ranged from 1 to 9 months (median 5) for the 20 IF patients, and from 1 to 30 months (median 4) for the 55 patients who achieved CR1. A variety of conditioning regimens were used, but most (80%) included total body irradiation. Five types of alloHSCTs were employed: matched unrelated in 37 (50%), matched related in 28 (38%), mismatched unrelated in 7 (10%), and mismatched related and unknown (1 each (1.4%)). Stem cells sources were bone marrow in 50 (67%), umbilical cord blood in 14 (19%) and peripheral blood in 11 (15%). Multivariate analyses on all 75 patients (adjusting for treatment arm and risk group, and using time-dependent covariates for time to HSCT) showed worse outcomes for those who received alloHSCT versus chemotherapy [Hazard ratio 3.46 (95% Confidence Interval 1.39 - 8.60); P = 0.008]. For IF patients, there was no difference in outcome for those receiving chemotherapy versus alloHSCT [Hazard Ratio 0.75 (95% CI 0.27-2.14); P = 0.60]. Centrally determined ETP status was available for 1123 (81%) of the subjects (Table), which were categorized as ETP (11%), Near ETP (17%) and Not ETP (72%) (Wood, BL: Blood 2014: [21]1). Most patients were not taken off therapy during induction, but among those who were and had ETP/Near ETP, 21 of 28 (75%) received alloHSCT versus 71 of 251 (28%) who received chemotherapy alone (Fischer's exact test, P <0.001). In multivariate analyses adjusting for ETP status, alloHSCT (n=66) was associated with inferior EFS compared to chemotherapy [Hazard ratio 2.81 (95% CI of 1.49-5.31); P = 0.001], and ETP status did not have a statistically significant impact on EFS [Hazard Ratio 1.36 (95% CI of 0.87-2.120; P = 0.18]. Conclusions: Our findings showed that only ~5% of participants in AALL0434 received alloHSCT, and that alloHSCT was employed in about half of those patients with IF. There was no EFS advantage for patients who failed induction and subsequently received alloHSCT. Patients were taken off protocol therapy and transplanted for a variety of reasons, which introduced heterogeneity. However, compared to those who received alloHSCT off therapy, we found that survival advantages favored those who received chemotherapy, regardless of ETP status. Table. Table. Disclosures No relevant conflicts of interest to declare.

scholarly journals Autologous Stem Cell Transfusions on Multiple Days in Patients with Multiple Myeloma - Does It Matter?

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3252-3252
Author(s):  
Thomas Pabst ◽  
Sebastian Moser ◽  
Ulrike Bacher ◽  
Barbara Jeker ◽  
Behrouz Mansouri Taleghani ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Conflicts Of Interest ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Cd34 Cells ◽  
The Impact

Introduction: Autologous stem cell transplantation (ASCT) following high-dose chemotherapy (HDCT) is a cornerstone in the standard first-line treatment in myeloma (MM) patients. Freezing of the hematopoietic stem cells (HSC) to bypass the time between stem cell collection and completion of HDCT is crucial for this process. Due to the vulnerability of HSC, adding of anti-freezing agents such 5-10 vol% dimethyl-sulfoxide (DMSO) to hematopoietic stem cells is mandatory. DMSO exerts toxic effects after administration, and toxicity of DMSO is dose-related. However, guidelines for this procedure are missing, and transplant centers have implemented varying limitations of maximum total DMSO administration, ranging from 20-70 g per day. At our center, the maximum transplant volume is 300 mL per day with DMSO at 5 vol%. For patients with transfusion volumes above these limits, the transplant procedure is split over several days. Methods: In this single center study, we retrospectively analyzed the impact of multiple day transplantation procedures on survival rates and hematological recovery in 271 patients with MM patients undergoing first melphalan-based ASCT. Results: 244 (90%) received ASCT within a single day, and this group was termed Tx1. The Tx2-3 group comprised 23 patients receiving stem cells on 2 days, and four patients on 3 days. Both groups (Tx1 and Tx2-3) did not differ in clinical characteristics or number/types of induction therapy lines. The remission status pre-transplant was comparable. Plerixafor was given more frequently in Tx2-3 than Tx1 (p=0.0715). At the day of SC collection, peripheral CD34+ counts were lower in Tx2-3. The final administered autograft volume was higher in Tx2-3 patients. The amount of transplanted CD34+ cells/kg b.w. was lower in the Tx2-3 group, mirroring poorer mobilization of CD34+ cells (p<0.0001). The median recovery for neutrophils was 13 days for Tx2-3 and 12 days for Tx1 (p=0.0048), and for platelets 18 versus 14 days (p=0.0004). Tx2-3 patients had longer median hospitalization duration (23 versus 19 days; p=0.0006). The median follow-up was 56 months. Relapse-free survival (RFS) was 39 months, and 169 relapses (62%) occurred so far. Median OS was 91 months, and 82 patients (30%) have died during follow-up. Tx2-3 patients had shorter median RFS (21 versus 40 months for Tx1; p=0.0245), and shorter median OS with 55 versus 93 months (p=0.0134) (Figure 1). Conclusions: Our data suggest that multiple day transplantation is associated with poor CD34+ mobilization and is observed in roughly 10% of myeloma patients. Patients with multiple day transplant procedures had later neutrophil and platelet engraftment, longer hospitalization duration, more febrile episodes, and inferior OS and RFS. This suggests to consider myeloma patients with the need for multiple day transplantation as a patient group at increased risk that needs enhanced surveillance strategies. Disclosures No relevant conflicts of interest to declare.

scholarly journals Intensification of Early-Phase Therapy to Diminish the Prognostic Effect of Myeloid Antigen Expression in Infants with KMT2A-Rearranged Acute Lymphoblastic Leukemia: A Report from the JPLSG MLL-10 Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2384-2384
Author(s):  
Yuki Arakawa ◽  
Takashi Ishihara ◽  
Takako Miyamura ◽  
Takao Deguchi ◽  
Masashi Sanada ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Early Phase ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Age Distribution ◽  
Central Nervous System Involvement ◽  
High Dose ◽  
Pediatric Leukemia ◽  
Hematopoietic Stem ◽  
Significant Difference

Abstract Background KMT2A-rearranged acute lymphoblastic leukemia (KMT2A-r ALL) is a rare and dismal disease in infants. Despite restriction of the indication of allogeneic hematopoietic stem cell transplantation to the high-risk group (patients aged &lt;180 days with KMT2A-r ALL or central nervous system involvement), adoption of an Interfant-06-based induction therapy with stricter age-related dosing followed by COG AALL0631-based post-remission chemotherapy with additional administration of high-dose cytarabine in the early intensification phase led to rapid clearance of minimal residual disease (MRD) in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) MLL-10 trial. The MLL-10 trial demonstrated an improved outcome of 66.2% in 3-year event-free survival (EFS) among infants with KMT2A-r ALL (Tomizawa D. Blood 2021). As the Interfant-06 study showed an association between the expression levels of myeloid markers (MM) and poor MRD clearance at end of induction (EOI) and a high relapse rate (Stutterheim J, J Clin Oncol.2021), we analyzed the significance of MM expression in the MLL-10 cohort and its association with prognosis. Methods We analyzed and compared the MM expression (defined as at least one positive marker [with a positive blast subset ≥ 10%] among CD117, CD13, CD33, and CD65/CD15) by using flow cytometry (FCM) in infants with KMT2A-r ALL who were registered in the JPLSG MLL-10 trial. We also compared the results of immunoglobulin/T-cell receptor (Ig/TCR) gene-based polymerase chain reaction (PCR)-MRD analyses or 4-color FCM-MRD assay between the MM-positive and MM-negative groups at EOI and end of early consolidation. The Ig/TCR-MRD results were classified as negative if &lt;5 × 10 −4 and positive if ≥5 × 10 −4, while the FCM-MRD results were classified as negative if &lt;0.01% and positive if ≥0.01%. We prioritized PCR-MRD and used FCM-MRD when we could not make a primer for PCR-MRD. The presence of MRD was not used as a basis for choosing the appropriate therapy. Results and Discussion Among the patients with KMT2A-rALL, 74 were included in this study, excluding one who was not evaluated with FCM at diagnosis. Of these patients, 42 were MM-positive and 32 were MM-negative. The 3-year EFS rates of the MM-positive and MM-negative patients were 62.3% (95% confidence interval [CI], 45.5-75.3) and 70.0% (95% CI, 50.3-83.1), respectively (p = 0.61). Their 3-year overall survival rates were 80.6% (95% CI, 65.0-89.8) and 87.5% (95% CI, 70.0-95.1), respectively (p = 0.74). The numbers of MM-positive and MM-negative patients according to age group are summarized in Table 1, and the difference in age distribution between the two groups was not significant. The MRD statuses of the patients at EOI in the two groups are also summarized in Table 1. No significant difference in MRD clearance was found between the MM-positive and MM-negative groups. Conclusion In this study, we found no significant difference in survival rate between the MM-positive and MM-negative groups. The MM expression was not a prognostic marker in the infants with KMT2A-r ALL in the MLL-10 cohort. We believe that rapid MRD clearance in the early phase of treatment with enhanced chemotherapy would have the greatest contribution to the improvement of prognosis. In this study, the MM-positive patients from the MLL-10 cohort might have benefited from early-phase treatment intensification in terms of MRD clearance. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Identification and Modeling of TEL-AML1 (ETV6-RUNX1) Molecular Signature In Acute Lymphoblastic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2500-2500
Author(s):  
Gregory Miles ◽  
Gunaretnam Rajagopal ◽  
Roger Strair ◽  
Hatem E Sabaawy
Keyword(s):  
Cell Cycle ◽  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Molecular Signature ◽  
Transgenic Zebrafish ◽  
Hematopoietic Stem ◽  
Childhood All ◽  
Leukemia Development

Abstract Abstract 2500 Despite high cure rates for childhood ALL, treatment failure remains a formidable problem. TEL-AML1 (ETV6-RUNX1), the product of t (12;21) translocation, is the most common cytogenetic abnormality in childhood cancer, and is detected in 25–30% of precursor B-cell (pre-B) acute lymphoblastic leukemia (ALL) in children, and in small percentage of adult ALL. Considerable experimental and clinical evidence indicate that the TEL-AML1 fusion is insufficient by itself for leukemic transformation. First, monozygotic twins had the same prenatal TEL-AML1 sequence, but different latency and/or no leukemia development. Second, we have previously established transgenic zebrafish expressing TEL-AML1. These TEL-AML1 transgenic zebrafish have hematopoietic stem cell (HSC) expansion, and develop pre-B ALL at low penetrance, and after prolonged latency. Similarly, transgenic mice expressing TEL-AML1 did not develop pre-B ALL, but showed HSC expansion. Third, retroviral-mediated TEL-AML1 gene transfer into murine HSCs resulted in a preleukemic state, and the incidence of leukemia increased with additional mutation. Here, we report on the identification of a TEL-AML1-specific leukemic signature in ALL cases, and modeling of these mutations in dual and compound transgenic zebrafish. First, we performed meta-analyses of ÓALL compendiumÕ of molecular signatures and expression profiles of 990 ALL cases from six studies, measuring the expression of 14,145 genes in 475 arrays. The normalized data were imported into the Ingenuity Pathway Analysis (IPA) software to identify TEL-AML1-related pathways. We determined a TEL-AML1-specific signature that was organized into modules that are induced or suppressed, based on involvement in several biological pathways comprising the hallmarks of cancer. These analyses identified modules of cell differentiation, cell proliferation, apoptosis, autophagy, cell cycle regulation, and lymphocyte development as the most common modules associated with TEL-AML1. The signature was confirmed using additional microarray analyses, in combination with Q-PCR, and western blotting from the same cases. Similar analyses of marrow cells from transgenic zebrafish with ALL identified 1,128 upregulated and 936 down-regulated genes with 27 genes common with the human TEL-AML1 signature. We next isolated the zebrafish homologues of several induced signature genes to generate dual and compound transgenic zebrafish, and to investigate the effects of their overexpression on TEL-AML1 leukemia development. Analyses of established transgenic fish demonstrate leukemia-enhancing effects of signals within the proliferation and cell cycle modules. These studies provide a model to understand the role of the TEL-AML1 fusion and the secondary mutations required for leukemia development, and might present a rational for leukemia combination therapy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Impact of Mantle Cell Lymphoma Contamination of Autologous Stem Cell Grafts on Outcome After High-Dose Chemotherapy

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2558
Author(s):  
Malte Roerden ◽  
Stefan Wirths ◽  
Martin Sökler ◽  
Wolfgang A. Bethge ◽  
Wichard Vogel ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mantle Cell Lymphoma ◽  
Clinical Decision Making ◽  
Cell Lymphoma ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Mantle Cell ◽  
Autologous Grafts

Novel predictive factors are needed to identify mantle cell lymphoma (MCL) patients at increased risk for relapse after high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HDCT/Auto-HSCT). Although bone marrow and peripheral blood involvement is commonly observed in MCL and lymphoma cell contamination of autologous stem cell grafts might facilitate relapse after Auto-HSCT, prevalence and prognostic significance of residual MCL cells in autologous grafts are unknown. We therefore performed a multiparameter flow cytometry (MFC)-based measurable residual disease (MRD) assessment in autologous stem cell grafts and analyzed its association with clinical outcome in an unselected retrospective cohort of 36 MCL patients. MRD was detectable in four (11%) autologous grafts, with MRD levels ranging from 0.002% to 0.2%. Positive graft-MRD was associated with a significantly shorter progression-free and overall survival when compared to graft-MRD negative patients (median 9 vs. 56 months and 25 vs. 132 months, respectively) and predicted early relapse after Auto-HSCT (median time to relapse 9 vs. 44 months). As a predictor of outcome after HDCT/Auto-HSCT, MFC-based assessment of graft-MRD might improve risk stratification and support clinical decision making for risk-oriented treatment strategies in MCL.

Sign in / Sign up

Export Citation Format

Share Document