Clofarabine with Topotecan, Vinorelbine, and Thiotepa (TVTC) in Children and Young Adults with Relapsed or Refractory Acute Myeloid Leukemia

Abstract Background: Relapsed or refractory pediatric acute myeloid leukemia (AML) is an unfortunate reality in approximately 40% of children and young adults diagnosed with AML. Therapeutic options are limited in this heavily pre-treated patient population, many of whom have reached lifetime recommended doses of anthracycline chemotherapy. Non-anthracycline based salvage regimens are crucial to these patients who are at significant risk of life-threatening cardiotoxicity. We previously reported results of a phase 2 trial of a Clofarabine-based regimen with Topotecan, Vinorelbine, and Thiotepa (TVTC) in a cohort of patients with AML. Herein, we report on an expanded cohort of AML patients treated at Memorial Sloan Kettering Cancer Center (MSKCC) since 2007. We report our center's experience using a Clofarabine-based regimen with Topotecan, Vinorelbine, and Thiotepa (TVTC), its overall response rate defined as complete remission (CR) and its use as a bridge to hematopoietic stem cell transplant (HSCT). Patients and Methods: All patients <25 years of age with relapsed/refractory AML, defined as >10% bone marrow involvement, who were treated with the phase 2 recommended schedule of TVTC were included in this analysis. Patients received the TVTC regimen with Topotecan 1 mg/m2/day (120 hour continuous infusion, Days 0-4), Vinorelbine 20 mg/m2/dose (Days 0, 7, 14), Thiotepa 15 mg/m2/dose (Day 2), and Clofarabine 40 mg/m2/day (Days 3-7). The regimen could be administered without hospitalization in patients who did not require hospitalization for other reasons. Most patients received antimicrobial prophylaxis starting on Day 8 with Levofloxacin and fungal prophylaxis with either Posaconazole or Voriconazole. GCSF 5mcg/kg/day was initiated on Day 8. Bone marrow evaluation was performed at the point of hematologic recovery to assess response. Overall response rate (ORR) was defined as complete remission (CR) plus complete remission without platelet recovery (CRp). Results: A total of 29 patients with relapsed (n=19) or refractory (n=10) AML were treated since 2007. Eight patients (28%) had prior hematopoietic stem cell transplantation (HSCT). The ORR of the entire cohort was 59% (17/29). The ORR of patients with relapsed vs. refractory disease was 74% (14/19) and 30% (3/10), respectively. Seventeen of 29 patients (59%) received TVTC as a 1st re-induction regimen with 59% (10/17) of those patients achieving a CR/CRp. The remaining 12 patients had TVTC as 2nd or greater regimen with 58% (7/12) of those patients achieving a CR/CRp. Among the 17 total responders in the cohort, 13 (76%) proceeded to HSCT. Of those who proceeded to HSCT, 8 of 13 are alive today (62%). Median time since HSCT is 66 months (range 14 to 107 months). The most common adverse effects were febrile neutropenia in 20 out of 29 patients (69%) which was Grade 3 or less, 3 of 29 patients (10%) with Grade 4 or greater febrile neutropenia requiring ICU admission. One patient developed an abdominal mucormycosis infection. One patient developed bone marrow aplasia and died due to sepsis 45 days after receiving TVTC. Conclusions: TVTC is an active regimen for children and young adults with relapsed/refractory AML, with an acceptable toxicity profile . Non-anthracycline containing salvage regimens are especially important as patients usually receive >400mg/m2 daunorubicin equivalents during frontline therapy. The majority of responders were successfully bridged to HSCT without exposure to additional anthracycline, with approximately half of these patients demonstrating long-term survival. TVTC warrants further exploration as a re-induction regimen in a larger cohort of patients with relapsed/refractory AML. Disclosures Kobos: Janssen Research & Development: Employment.

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Dasatinib therapy for patients with Philadelphia-negative (ph-) myeloproliferative disorders (MPDs), including systemic mastocytosis

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.7086 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 7086-7086

Author(s):

S. Verstovsek ◽

E. Atallah ◽

D. Thomas ◽

J. Cortes ◽

F. Ravanid-Kashami ◽

...

Keyword(s):

Bone Marrow ◽

Complete Remission ◽

Tyrosine Kinases ◽

Overall Response Rate ◽

Response Rate ◽

Kinase Inhibitor ◽

Systemic Mastocytosis ◽

Fusion Transcript ◽

Kit Mutation ◽

Overall Response

7086 There are no curative medical therapies for Ph- MPDs. Over last several years several of the MPDs have been associated with the abnormal expression of selected tyrosine kinases (e.g. c-kit in SM) and others are suspected to be involved too. Therefore, we engaged in conducting a Phase II study with dasatinib, an orally available multi targeted kinase inhibitor, for patient with Ph- MPDs. Dasatinib is administered at 70 mg PO BID continuously (one month equals one cycle). Response is assessed every 3 cycles, and the therapy is discontinued in those without response after 6 cycles of therapy. Patients are observed for any toxicity; in such cases the dose of dasatinib is adjusted to 50 mg PO BID, then to 40 mg PO BID, or discontinued. The study is ongoing and has enrolled 55 patients; 44 are evaluable for response and toxicity, including 24 with SM (6 with aggressive SM, 4 with SM and associated hematologic non-mast cell disease and 14 with indolent SM with uncontrolled symptoms despite optimal supportive care measures), 10 CIMF, 6 HES, 3 unclassifiable MPD and one PV. Median age is 65 years (range, 27–75); 25 males and 19 females. The overall response rate in SM was 42% (10 pts). Of those, two patients (8%) achieved complete remission, one with SM-CIMF, and one with SM-HES. Both were c-KIT mutation negative and had low, not significant tryptase levels. Both were anemic (Hb 9.4g/dL) and failed erythropoietin therapy, and had abnormal WBC differential; one had low platelets (90×109/L). Symptoms related to SM improved significantly in additional 8 patients, however, no significant response in percentage of bone marrow mast cells or blood tryptase levels have been observed so far. The 6 patients with HES had previously failed imatinib therapy and had no evidence of the FIP1L1-PDGFRA fusion transcript; one achieved complete remission (normalization of blood and bone marrow eosinophil percentage) while others did not respond. No responses have been recorded in patients with CIMF, PV and unclassifiable MPD. No grade 4 toxicity has been observed. Dasatinib is active in SM (overall response rate 42%) mainly by improving symptoms. Updated clinical results on all enrolled patients will be presented. No significant financial relationships to disclose.

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Personalized Approach To Treatment of Acute Myeloid Leukemia Using a High-Throughput Chemosensitivity Assay

Blood ◽

10.1182/blood.v122.21.483.483 ◽

2013 ◽

Vol 122 (21) ◽

pp. 483-483 ◽

Cited By ~ 2

Author(s):

Ka Yee Yeung ◽

C. Anthony Blau ◽

Vivian G. Oehler ◽

Su-In Lee ◽

Christopher P. Miller ◽

...

Keyword(s):

Bone Marrow ◽

Complete Remission ◽

High Throughput ◽

Myeloid Leukemia ◽

In Vitro Cytotoxicity ◽

Personalized Approach ◽

New Diagnosis ◽

Acute Myeloid ◽

Refractory Aml

Most patients with acute myeloid leukemia either relapse or fail to respond to initial therapy. Moreover, each patient’s AML contains multiple mutations that although varying from one population to another, are unique to that individual, prompting development of individualized approaches to AML therapy. We have devised a high-throughput sensitivity assay for 160 drugs; 45 are FDA approved and 115 are investigational, representing multiple mechanisms of action and signaling pathways. 30 primary patient blood marrow samples and 15 acute leukemia cell lines have been analyzed. Peripheral blood blasts from individual patients were thawed, viable cells isolated and purified to >80% using magnetic bead separations. In vitro chemotherapy cytotoxicity testing is performed in a 384 well high throughput format, with eight concentrations of each drug. The output is cell survival assessed via a luminescent detection method after a 4-day incubation with various drugs. Fitted curves (idbs XLfit) were derived from plots of survival versus drug concentrations used in the study. Leukemia cells are tested adherent to coated plates to mimic adhesion in the bone marrow microenvironment, a property that confers drug resistance. The assay exhibits excellent reproducibility from independently thawed samples from the same patients, with a Spearman correlation coefficient of 0.9 (p=1.6 X 10-141). Gene expression microarrays were also performed for the same 30 patients. Our assay of the 30 patients revealed that there were over 50 drugs that exhibited cytotoxicity in at least some patients. There was wide variation in the drug sensitivity patterns exhibited by the patient blasts samples, and each was unique. Notably, all patient samples were susceptible to several drugs with IC50s in the range that might predict clinical response. For patients who achieved complete remission, we showed statistically significant association with in vitro cytotoxicity in response to 7 drugs that are commonly employed to treat AML, including mitoxantrone (p=0.002 for 0.1 µM, p=0.01 for 0.3 µM), clofarabine (p=0.0009 for 0.1 µM, p=0.003 for 0.3 µM, p=0.007 for 1µM), daunorubicin (p=003 for 0.1 µM, p=0.005 for 0.3 µM), etoposide (p=0.02 at for 0.1 µM, p=0.01 for 0.3 µM, p=0.01 for 1 µM), and fludarabine (p=0.05 for 0.3 µM, p=0.002 for 1 µM). In addition, we used a multivariate statistical method to identify drug combinations that are effective in predicting the complete remission of AML patients. In particular, we found that the in vitro cytotoxicity data of a combination of three drugs (BAY 11-7085, TPCA-1, ON 01910.Na) are more predictive of the complete remission of patients compared to using each of these drugs individually (i.e. 91.2% accuracy compared to 84.8%, 84.2%, 79.1% respectively). We also performed linear regression analyses to study the relationship between in vitro cytotoxicity in the high throughput screen of each drug versus the patients’ clinical features (including complete remission, having received the tested drug, new diagnosis vs. relapse status, age, gender, bilirubin, albumin, lactate dehydrogenase, white blood count, platelet count, blast, absolute neutrophil count, % bone marrow blasts, hemoglobin, fibrinogen, cytogenetics risk category). The following patients’ clinical features showed significant correlations with the in vitro cytotoxicity of our assays in selected drugs: complete remission for mitoxantrone (p= 0.04 for 0.3 µM), flavoperidol (p= 0.02 0.1 µM), and fludarabine (p= 0.01 0.3 µM, p=0.02 for 1 µM); drug the patient received for clofarabine (p= 0.03 for 0.3 µM, p=0.007 for 1 µM); new diagnosis vs. relapse for clofarabine (p= p= 0.02 for 0.3 µM, p=0.006 for 1 µM). This assay serves as the basis for a new clinical trial (ClinicalTrials.gov Identifier: NCT01872819) now open to enrollment for “personalized” leukemia therapy, for which patients with refractory AML are assigned drugs based on the results of this test. This new personalized approach to individualized therapy for refractory AML may provide novel drugs to patients and new insights into leukemia drug resistance. Disclosures: No relevant conflicts of interest to declare.

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Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in Children and Young Adults with Chronic Myeloid Leukemia: A CIBMTR Cohort Analysis

Blood ◽

10.1182/blood.v124.21.2534.2534 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2534-2534 ◽

Cited By ~ 1

Author(s):

Sonali Chaudhury ◽

Nobuko HiJiya ◽

Zhenhuan Hu ◽

Rodney Sparapani ◽

Matt E. Kalaycio ◽

...

Keyword(s):

Young Adults ◽

Stem Cell ◽

Chronic Myeloid Leukemia ◽

Cell Transplantation ◽

Myeloid Leukemia ◽

Early Disease ◽

Hematopoietic Stem ◽

Allogeneic Hct ◽

Adjusted Analysis ◽

Children And Young Adults

Abstract Chronic myeloid leukemia (CML) in pediatrics is rare accounting for 2–3% of leukemias. Data on allogeneic hematopoietic cell transplantation (HCT) in this group is scarce. Since the introduction of tyrosine kinase inhibitors (TKI), HCT in patients with CML especially with early disease has decreased. Children and young adults have long life expectancies, lower morbidity with HCT and are likely to recieve prolonged TKI therapy with increased risk for complications. HCT for early disease may still benefit this population. We retrospectively evaluated outcomes in CML patients receiving myeoloablative HCT reported to the CIBMTR, comparing pediatric patients (n= 212) to young adults (n=200). Table 1 describes patient variables. 5 y overall survival (OS) and leukemia free survival (LFS) in <18 y was 71% (95%CI 65-77) and 51% (95%CI 43-58) respectively. In adjusted analysis, there was a statistically insignificant effect of prior TKI therapy on LFS (P=0.07), OS (0.06), transplant related mortality (TRM) (P=0.47) or relapse (P=0.88). Favorable factors for OS were early disease, matched sibling donors (MSD), bone marrow (BM) or cord blood (CB) grafts. LFS was superior with total body irradiation (TBI), non alemtuzumab based regimens and recent (>2006) HCTs. 5 year OS and LFS for the 18-25y group was 71 (95%CI 65-77)% and 53 (45-60)% respectively. In adjusted analysis there was no difference in OS (P=0.7), LFS (P=0.4) for 18-25y group compared to the pediatric group. Favorable factors for OS/DFS remained early disease, MSD and BM grafts. Allogeneic HCT outcomes were comparable in children and young adults. HCT should remain an option for young patients with CML especially with a MSD using TBI containing regimens with BM as the stem cell source. We could not show an advantage for TKI use prior to HCT. Long term toxicities of TKI and allogeneic HCT need to be further evaluated in this group. Table1 Description of variables for Allogeneic HCT in CML Table1. Description of variables for Allogeneic HCT in CML Figure 1 Adjusted OS and LFS for <18y vs. 18-25y Figure 1. Adjusted OS and LFS for <18y vs. 18-25y Disclosures HiJiya: Pfizer: Consultancy; Jazz: Consultancy; Enzon: Consultancy; Sanofi: Consultancy.

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Preemptive Administration of Ruxolitinib Rapidly Ameliorate Gvhd after Allo-Hematopoietic Stem Cell Transplantation: A Single-Center Retrospective Study

Blood ◽

10.1182/blood-2019-128003 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3293-3293

Author(s):

Kangni Lin ◽

Minmin Chen ◽

Qian Li ◽

Jinhua Ren ◽

Haojie Zhu ◽

...

Keyword(s):

Stem Cell ◽

Retrospective Study ◽

Hematopoietic Stem Cell Transplantation ◽

Complete Remission ◽

Stem Cell Transplantation ◽

Overall Response Rate ◽

Response Rate ◽

Single Center ◽

Hematopoietic Stem ◽

Conditioning Regimens

Objective: Clinical benefit with ruxolitinib as a salvage therapeutic agent in steroid-refractory acute graft-versus-host disease (aGVHD) has been reported. The purpose of this study is to explore the efficacy and safety profile of preemptive administration of ruxolitinib for patients with GVHD after hematopoietic stem cell transplantation (HSCT), and to determine the optimal timing of start of ruxolitinib treatment. Methods: We conducted a single-center retrospective study to analyze the overall response rate at day 28 and the amelioration of GVHD after preemptive treatment of ruxolitinib in patients with GVHD post-HSCT. A total of 35 patients (26 males/ 9 females) with GVHD (30 aGVHD/ 5 cGVHD) treated at Fujian Medical University Union Hospital (Fuzhou, China) from July 2016 to April 2019 were enrolled. All patients received conditioning regimens including ATG, cyclosporine A, methylprednisolone, methotrexate mycophenolate mofetil w/o basiliximab for prevention of GVHD. Ruxolitinib was administered orally at 10 mg twice daily for patients ≥ 40 kg or 5 mg twice daily if <40 kg. The patients were divided into 3 groups according to the starting time of GVHD treatment with the preemptive ruxolitinib: shorter than 3 days (≤3 day,13, 37.1%), between days 3-7 (3-7 days,10, 28.6%) and more than 7 days(>7 days,12, 34.3%). Treatment responses of ruxolitinib and the safety are compared among groups. Results: These three groups were well matched demographically. There were no significant differences in conditioning regimens, donor types, CD34+ cells infusion, GVHD prophylaxis regimens and primary treatment among 3 groups. The median time to response of ≤3 days group, 3-7 days group and >7 days group was 20.5 (6-43) , 19.5 (2-107) and 20.5 (9-60) days, respectively. The ≤3 d group showed a best overall response rate (ORR) and complete remission rate (CRR) at day 28 after treatment than 3-7 d group and >7 d group (ORR: 92.3% vs 90.0% vs 83.3%, P=0.361; CRR: 46.2% vs 40.0% vs 25.0%, P=0.512 ). The cumulative complete remission rates among 3 groups were 58.5% (≤3 d group), 86.7% (3-7 d group) and 25% (>7 d group), respectively (P=0.096). The severity of GVHD were significantly ameliorated at day 28 in ≤3 d group than the other 2 groups ( 92.3% vs 70.0% vs 50.0%, P=0.064), and moreover, the clinical GVHD scores dropped significantly in ≤3 d group than >7 d group (-1.54 grade vs -0.75 grade, P=0.041) at day 28 after treatment. Incidence and severity of adverse reactions did not differ significantly between groups (P>0.05). Conclusion: When preemptive administration ruxolitinib is initiated rapidly, remarkable efficacy on amelioration of GVHD can be achieved without significant adverse effects. Larger randomized trials are needed to confirm efficacy. Disclosures No relevant conflicts of interest to declare.

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Results of Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia of the FAB M0 Subtype in First Complete Remission: A Survey of the Acute Leukemia Working Party of the European Bone Marrow Transplant Group (EBMT).

Blood ◽

10.1182/blood.v104.11.5131.5131 ◽

2004 ◽

Vol 104 (11) ◽

pp. 5131-5131

Author(s):

Andree-Laure Herr ◽

Myriam Labopin ◽

Rosy Reiffers ◽

Donald Bunjes ◽

Didier Blaise ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Complete Remission ◽

Myeloid Leukemia ◽

Hematopoietic Stem ◽

First Complete Remission ◽

Acute Myeloid

Abstract Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients with acute myeloid leukemia (AML). AML of the FAB M0 subtype is rare, often associated with a complex karyotype and a poor prognosis. Results of HSCT for this AML subtype have never been reported separately from other subtypes. We did a survey of the results of 274 HSCT in adults with M0 AML in first complete remission (CR1), performed in EBMT centres since January 1990 until 2002. One hundred fifty patients were transplanted with an HLA identical donor (HLA-id), 30 with an HLA-matched unrelated donor (MUD) and 94 received an autologous transplant (auto). The median age was 45 years (16–71), the median interval from diagnosis to HSCT was 4 months for HLA-id, 6 months for MUD and 5 months for auto HSCT. The median follow-up time (range) was 20 months (1–109), 12 (2–53) and 10 months (1–96) for HLA-id, MUD and auto-HSCT respectively. The source of stem cells was peripheral blood stem cells for 67% of cases, and bone marrow for the remaining. The majority of grafts were non-T-cell depleted. Acute GVHD (grade I–IV) occurred in 56% of HLA-id and in 64% of MUD cases. The table shows the outcomes at two years according to the type of transplant. In conclusion, outcomes after HLA identical HSCT and MUD in adult patients with AML FAB subtype M0 in CR1 are encouraging. In comparison to allogeneic transplant cases, LFS is decreased in patients receiving an autologous transplant due to a high relapse incidence, reflecting the probable role of a graft-versus-leukemia effect in this FAB subtype. Results of HSCT in AML M0 CR1 patients Outcomes HLA-id n=150 MUD n= 30 Auto n=94 LFS: leukemia free survival; OS: overall survival; RI: relapse incidence; TRM: treatment-related mortality 2y LFS 50% 45% 33% 2y OS 58% 50% 49% 2y RI 25% 40% 57% 2y TRM 24% 14% 9%

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Clinical Activity of Azacitidine In Combination with the Oral mTOR Inhibitor Everolimus (RAD001) In Relapsed and Refractory AML: Interim Analysis of a Phase Ib/II Study

Blood ◽

10.1182/blood.v116.21.3301.3301 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3301-3301

Author(s):

Andrew H Wei ◽

Sonali Sadawarte ◽

John Catalano ◽

Anthony P. Schwarer ◽

Sharon Avery ◽

...

Keyword(s):

Bone Marrow ◽

Research Funding ◽

Overall Response Rate ◽

Mtor Inhibitor ◽

Response Rate ◽

Clinical Activity ◽

Cell Transplant ◽

Phase Ib ◽

Overall Response ◽

Refractory Aml

Abstract Abstract 3301 Background Although the demethylating agent azacitidine has an established role in myelodysplastic syndromes and encouraging activity in oligoblastic acute myeloid leukemia (AML), information regarding its role in relapsed and refractory AML is still emerging. The French ATU reported an overall response rate (ORR; CR/CRi+PR) in relapsed and refractory AML of 11% (Itzykson et al. ASH 2009 #1054). In a similar population, azacitidine salvage therapy produced a CR/CRi rate of 19% (Ayari S, et al. ASH 2009 #2044). Rapamycin, an inhibitor of the AKT downstream target mammalian Target Of Rapamycin (mTOR), is reported to specifically target leukemic stem cells and orally bioavailable rapamycin derivatives, such as everolimus (RAD001), are in active clinical development. Clinical responses with single agent everolimus in relapsed, refractory AML, however, have been modest (Yee et al, Clin Cancer Research 2006 and Boehm et al, European Journal of Internal Medicine 2009). Aim Building on our experience combining everolimus with low dose cytarabine (submitted to ASH, 2010), we have sought to investigate the feasibility and preliminary efficacy of combining everolimus with azacitidine in relapsed and refractory AML. Methods Phase Ib/II open label dose escalation study. Patients were treated with azacitidine 75 mg/m2 s.c. daily on days 1–5 and 8–9 of each 28-day cycle with either 2.5, 5 or 10 mg everolimus orally on days 5–21 for a maximum of 12 cycles. Results This preliminary analysis includes 20 patients (M 14, F 6), median age 64 years (range 17–76) receiving 2.5 mg (n=6), 5 mg (n=12) or 10 mg (n=2) everolimus. 9 (45%) had chemotherapy refractory and 11 (55%) relapsed AML after 1 (n=8), 2 (n=10) or 3 (n=2) previous lines of therapy. 7/17 (41%) had poor risk and 10/17 (59%) intermediate risk cytogenetics. 6/19 (32%) had secondary AML. The overall response rate (ORR) in 14 evaluable patients was 36% (2 CR, 3 PR). Stable disease (SD) was observed in 7 (50%) patients and 2 (14%) had progressive disease. Absolute bone marrow blast reductions from baseline in the 5 responders ranged from 9 to 88% (Figure 1). Grade 3/4 non-hematologic toxicities are summarized as follows: 2.5 mg everolimus cohort- septicemia (n=1) and mucositis (n=1, dose limiting toxicity; DLT), 5 mg everolimus cohort- septic arthritis (n=1, DLT). Febrile neutropenia during the first cycle of therapy was reported in 5/20 (25%). Safety analysis in the 10 mg everolimus cohort is ongoing. With a median follow up of 82 days, 30 day mortality was 0%. Enrolment continues to a planned 40 patients. Of interest, 2 out of 3 patients with FLT3-ITD+ AML refractory to high-dose cytarabine and antracyclines, had a striking reduction in bone marrow blasts after commencing azacitidine + everolimus (2.5 mg) therapy, with the absolute blast count falling from 95% to 16% and 92% to 5%, respectively, and lasting for at least 5 months in both. One of these patients has so far proceeded to allogeneic stem cell transplant (allo-SCT). Another patient with 3rd relapse of AML after failing allo-SCT, achieved CR after 3 cycles of treatment with azacitidine + everolimus (2.5 mg) and remains in CR after 157 days. Conclusion In relapsed and refractory AML, azacitidine in combination with the mTOR inhibitor everolimus was well tolerated and demonstrates substantial clinical activity in this advanced AML population. Further evaluation of this promising combination is ongoing. Disclosures: Wei: Novartis: Advisory board, Research Funding; Celgene: Research Funding. Off Label Use: AML therapy. Catalano:Celgene: Research Funding; Roche: Honoraria, Research Funding, Travel Grants.

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Chemotherapy for induction of remission of childhood acute myeloid leukemia followed by marrow transplantation or multiagent chemotherapy: a report from the Childrens Cancer Group.

Journal of Clinical Oncology ◽

10.1200/jco.1994.12.1.127 ◽

1994 ◽

Vol 12 (1) ◽

pp. 127-135 ◽

Cited By ~ 69

Author(s):

M E Nesbit ◽

J D Buckley ◽

S A Feig ◽

J R Anderson ◽

B Lampkin ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Young Adults ◽

Bone Marrow Transplantation ◽

Marrow Transplantation ◽

Myeloid Leukemia ◽

Cancer Group ◽

Significant Difference ◽

Children And Young Adults ◽

Acute Myeloid

PURPOSE In an effort to evaluate the usefulness of bone marrow transplantation, the Childrens Cancer Group (CCG) initiated a multiinstitutional study comparing bone marrow transplantation versus chemotherapy after successful induction of remission for previously untreated children and young adults with acute myeloid leukemia. PATIENTS AND METHODS From 1979 to 1983, 508 patients were entered onto this study and 490 were treated. After induction, patients with an HLA mixed leukocyte culture (MLC)-compatible sibling underwent bone marrow transplantation. Patients not eligible for bone marrow transplantation were eligible for randomization to two chemotherapy maintenance regimens. All patients undergoing bone marrow transplantation were conditioned with cyclophosphamide and total-body irradiation (TBI). Methotrexate was used to prevent or modify graft-versus-host disease (GVHD). RESULTS Three hundred eighty-one patients achieved bone marrow remission (78%). Eighty-nine patients had an HLA/MLC-compatible sibling donor and were eligible for bone marrow transplantation, and 252 had no match. Comparison of survival estimates for patients eligible for transplantation versus not eligible at 3 years (52% v 41%), 5 years (50% v 36%), and 8 years (47% v 34%) showed a significant difference in favor of bone marrow transplantation (P < .05). Disease-free survival (DFS) demonstrated similar results. Application of a cure model to the results showed a better outcome for those eligible for transplantation (P = .04). Patients randomized between the two chemotherapy regimens did not show any significant difference between those treated with a continuous maintenance versus a cyclic regimen (P = .16). CONCLUSION Children and young adults who successfully achieved a remission with multiple-agent chemotherapy who had an HLA/MLC-compatible donor and were thus eligible for an allogeneic bone marrow transplant had better survival than those not eligible for transplantation.

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Phase 2 Study of 5 Days Azacytidine Priming Prior to Fludarabine, Cytarabine and G-CSF Combination for Patients with Relapsed or Refractory AML

Blood ◽

10.1182/blood-2018-99-114037 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5181-5181

Author(s):

Ibraheem H. Motabi ◽

Shahid Iqbal ◽

Syed Ziauddin A. Zaidi ◽

Belal Albtoosh ◽

Nawal Faiez Alshehry ◽

...

Keyword(s):

Bone Marrow ◽

Overall Response Rate ◽

Response Rate ◽

Complete Response ◽

Refractory Disease ◽

Curative Therapy ◽

Overall Response ◽

Remission Status ◽

The Mean ◽

Refractory Aml

Abstract Background: Acute Myeloid Leukemia (AML) is a group of heterogeneous clonal disorder of myeloid progenitor cells. Relapsed and refractory AML represent a clinical and therapeutic challenge to hematologist because of chemotherapy resistant disease and are associated with poor outcome. Allo-SCT is the only potentially curative therapy for such patients and is only possible after achieving second remission. FLAG is used more commonly and is associated with around 50%. We hypothesize that pretreatment with azacytidine will improve the overall response rate and remission status. Objectives : The primary objective of this study is to evaluate the overall response rate (ORR) of pretreatment with azacytidine followed by FLAG for the treatment of relapsed/refractory AML. Methods: This is prospective phase II study of patients with diagnosis of refractory/relapse AML at King Fahad Medical City, Riyadh, Saudi Arabia between January 2015 and July 2018. Patient confirmed to be relapse/refractory AML based on bone marrow biopsy results were included. Eligible patients received pretreatment with azacytidine for 5 days (days -5 to -1). The FLAG protocol was started on the next day after the completion of 5-azacytidine. G-CSF was started on day 0 (24 hours after last 5-azacytine dose) and continued for a total of seven days (days 0 to 6). Fludarabine and cytarabine was started on next day after G-CSF start day and continued daily for 5 days (days 1 to 5). Patients were followed up with daily clinical examination and labs until next bone marrow examination at count recovery up to day 35. The bone marrow sample was analyzed for cell cycle and global DNA methylation status before and after azacytidine treatment. The ORR is the proportion of the treated patients who achieved CR or Cri. The toxicity was graded base on the frequency of Adverse Events (the NCI-CTCAE version 4.0 scoring system). Results: Sixteen refractory/relapsed AML patients (5 females; 11 males) admitted to our Center from January 2105 to July 2018 were included in the study. Twelve patients were evaluable after exclusion of three patients from analysis based on exclusion criteria. One patient died during induction. The mean age was 39.38 ± 15.11 years. The mean WBC, hemoglobin, platelets, peripheral blood blasts, bone marrow blasts were 26.44 ± 23.15, 7.43 ± 1.55, 61.81 ± 85.20, 49 ± 30.36, and 57.36 ± 29.23 respectively at diagnosis. The mean bone marrow blasts were 42.09 ± 29.75 at relapse/refractory disease. Seven patient had normal Cytogentics. One patient had BCR (9q43), PML (15q22), RUNX1T1(8q22) & MLL (11q23) genes. Another one had EGR1 (5q31) deletion, while t(8;21) was found in another patient. One patient was positive for 7q31 deletion. Four out of twelve patients had abnormal molecular cytogentics including FLT3 -ITD, CEBPA, FLT3 -TKD mutation and KITD816V. No patient has extramedullary disease at diagnosis or relapse settings. Seven out of twelve patients had primary refractory disease while five patients had relapsed disease with 6 months' median duration of remission (Range 1.25-84). Nine patient received 3+7 induction regimen at diagnosis while three had ICE protocol. Eight out of twelve patients showed complete response (67%). Four out of five relapsed patients achieved complete response (80%) whereas four out of seven (57.14%) achieved complete response in refractory disease. Eight patients were referred for stem cell therapy. The most common toxicity was cytopenia and bacterial infections. One patient has left arm cellulitis whereas one had arthritis with myositis. All patients were successfully treated with antibiotics, one patient died during study period because of severe invasive fungal infection. Conclusion Our phase II study preliminary results indicate that the addition of Azacitidene prior to standard therapy can improve the overall response rate and remission status in relapsed/refractory AML. This may provide an opportunity to responding patients to proceed to curative therapy with stem cell transplant. Disclosures No relevant conflicts of interest to declare.

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Targeting the CXCR4 Pathway: Safety, Tolerability and Clinical Activity of Ulocuplumab (BMS-936564), an Anti-CXCR4 Antibody, in Relapsed/Refractory Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v124.21.386.386 ◽

2014 ◽

Vol 124 (21) ◽

pp. 386-386 ◽

Cited By ~ 28

Author(s):

Pamela S. Becker ◽

James M. Foran ◽

Jessica K. Altman ◽

Abdulraheem Yacoub ◽

Januario E. Castro ◽

...

Keyword(s):

Complete Remission ◽

Myeloid Leukemia ◽

Research Funding ◽

Response Rate ◽

Peripheral Circulation ◽

Infusion Reaction ◽

Clinical Activity ◽

Induction Failure ◽

Refractory Aml

Abstract Background: CXCR4 is a chemokine receptor over-expressed on > 75% of cancers, including myeloid leukemia blasts. Ulocuplumab (BMS- 936564) is a first in class, fully human IgG4 monoclonal antibody which inhibits the binding of CXCR4 to CXCL12, resulting in the mobilization of leukocytes from the bone marrow to the peripheral blood. Ulocuplumab also induces apoptosis of CXCR4+ cells in clinicial samples (i.e., leukemia blasts) and in in vitro experiments (e.g. in Tregs). It is thus hypothesized that Ulocuplumab may induce the mobilization and apoptosis of myeloid blasts & immunosuppressive cells which could improve the overall response rate to chemotherapy Objective: To conduct a first-in-man phase I dose escalation/ expansion trial to determine the safety, pharmacology, and clinical benefit of Ulocuplumab in relapsed/refractory AML Results: Seventy three subjects (median age, 58 yrs; range, 21-79 y) with relapsed/refractory AML were treated with Ulocuplumab and MEC [mitoxantrone, 8 mg/m2; etoposide , 100 mg/m2; and cytarabine, 1 g/ m2; i.v. d 1-5]. Thirty subjects in escalation received a single infusion of Ulocuplumab (doses of 0.3, 1, 3, or 10 mg/kg) one week prior to starting MEC and 3 additional weekly doses per MEC cycle thereafter (starting on Day 1). Ulocuplumab was escalated to a maximum of 10 mg/kg without any dose-limiting toxicity during monotherapy or in combination with MEC in the 1st cycle. In expansion phase, 43 patients were similarly treated with10 mg/kg Ulocuplumab and MEC. The overall complete remission and complete remission with incomplete blood count recovery rate (CR/CRi) was 51%. Subjects with first CR > 6 months had better ORR (16/23, 70%) than those with CR1 ≤6 months or primary induction failure (6/20, 30%). Of note, four subjects had CR/CRi after a single dose of Ulocuplumab monotherapy. Transient, mild/moderate thrombocytopenia was the only treatment-related AE documented with Ulocuplumab monotherapy. Only one subject presented a mild infusion reaction on Cycle 1 Day 1. The safety profile in combination with MEC was similar to MEC alone as was the 60 day all-cause mortality (16.3%). A median 2- and 5-fold mobilization of leukocytes and leukemic blasts into the peripheral circulation was reported at day 8, respectively. There was a trend demonstrating that higher CXCR4 expression on AML blasts correlated with a positive clinical response. Reversible and manageable hyperleukoctosis occurred in one subject. Conclusions: This study shows that the blockade of the CXCR4-CXCL12 axis with Ulocuplumab has antileukemic activity and safely improves the historic response rate achieved with MEC alone (i.e.,24-28%). Disclosures Becker: Bristol-Myers Squibb: Research Funding. Off Label Use: Etoposide is indicated in the management of refractory testicular tumors and small cell lung cancer. . Foran:Bristol-Myers Squibb: Research Funding. Altman:Bristol-Myers Squibb: Research Funding. Yacoub:Bristol-Myers Squibb: Research Funding. Castro:Bristol-Myers Squibb: Research Funding. Sabbatini:Bristol-Myers Squibb: Employment. Dilea:Bristol-Myers Squibb: Employment. Wade:Bristol-Myers Squibb: Employment. Xing:Bristol-Myers Squibb: Employment. Gutierrez:Bristol-Myers Squibb: Employment. Cohen:Bristol-Myers Squibb: Employment. Smith:Bristol-Myers Squibb: Research Funding.

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Aripiprazole in youth with intellectual disabilities: A retrospective chart study

Journal of Intellectual Disabilities ◽

10.1177/1744629520905175 ◽

2020 ◽

pp. 174462952090517

Author(s):

Eva Enneke Reurts ◽

Pieter W Troost ◽

Mariken Dinnissen ◽

Sam Reijnen ◽

Pieter J Hoekstra ◽

...

Keyword(s):

Young Adults ◽

Adverse Events ◽

Intellectual Disabilities ◽

Overall Response Rate ◽

Response Rate ◽

Open Label ◽

Serious Adverse Events ◽

Children And Young Adults ◽

Clinical Global Impression Improvement

A retrospective chart study of patients on open-label aripiprazole treatment was conducted in the Netherlands to add to the knowledge of aripiprazole in children and young adults with mild and borderline intellectual disabilities (IDs). Fifty-three youths, mean age 14.7 ± 3.4 years and mean IQ 64.5 ±13.8, were included. Treatment responders were defined as “much improved” or “very much improved” based on the Clinical Global Impression -Improvement scale. For 83% of the patients, disruptive behavior was the main target symptom. The overall response rate was 30% after 1–4 weeks and 69% after 5–8 weeks. The 5–8 weeks responders showed a response rate of 64% at 22–26 weeks. Mild adverse events were observed in 53% of the patients of which fatigue and weight gain were the most common. Seven patients (13.2%) discontinued because of adverse events. In 53 children and young adults with mild and borderline IDs, aripiprazole was effective in both the short and the long term. No serious adverse events were observed.

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