Indications For Stem Cell Transplantation Research Articles

Practical and Flexible Genome Profiling Study Using the Halo-Shape Annealing and Defer-Ligation Enrichment (HANDLE) System: HM-Screen-JAPAN02

Background Acute myeloid leukemia (AML) is known to have a relatively small number of genomic mutations compared to solid tumors. With the development and clinical application of drugs targeting genetic mutations involved in the pathogenesis of AML, the Japanese Society of Hematology has defined “fast-track mutations” as those that should be reported promptly due to clinical necessity. A multicenter genomic profiling study (HM-SCREEN-JAPAN01: HM01 study) was conducted to comprehensively sequence 406 DNA mutations and 265 RNA aberrations in 177 AML patients, suggesting its usefulness in clinical practice, but the turnaround time (TAT) until results are reported remains an issue (Hosono, et al. Cancer Sci, 2023). Aims We have launched the HM-SCREEN-JAPAN02 (HM02) study, a practice-oriented genome profiling study that improves on the previous HM01 study and uses a newly developed targeted sequencing method. The HM02 study adopted the novel Amoy Myeloid Panel® method, which uses the HANDLE (Halo-shape ANnealing and Defer-Ligation Enrichment) system to significantly shorten TAT and facilitate specimen submission, and was designed to be completed in 7 days from sequencing to reporting. The HM02 study allows mutation analysis at any treatment timing, such as at initial presentation, during treatment, or at relapse, as well as the capability to track clonal changes through repeat analysis; the HM02 study was designed to determine whether such flexible analysis is useful in determining treatment strategy. Results The study was conducted at 23 centers in Japan, enrolling a total of 154 cases from 2020 to 2022, with 191 samples analyzed to assess the usefulness of the study. Repetitive mutation analysis was performed in 21 cases, and clonal changes could be tracked. Among the mutations detected, we selected those that were determined to be pathogenic or likely pathogenic by ClinVar. Of the 154 cases analyzed, none of the pathogenic mutations were detected in 9 cases, and 6 were of the normal karyotype. The most frequently observed mutations were TET2 (51%), FLT3 (30%), TP53 (18%), and NPM1 (17%) (Figure 1). In multivariate analysis adjusted for age, gender, and stem cell transplantation status, TP53 and NRAS mutations were associated with higher risk for death (HR=6.82 and 14.98, respectively). Of the 19 cases in which pathological mutations were repeatedly investigated, 8 were useful in determining minimal/measurable residual disease (MRD) (2 cases of MRD loss and 6 cases of MRD retained), 6 cases showed the development of new clones and 5 cases showed clonal evolution, indicating that repeated mutation analysis can be used to evaluate detailed disease status. In terms of clinical utility, HM02 mutation analysis was useful in 62% of cases (98 of 158), particularly for risk assessment and determining the indication for stem cell transplantation (Figure 2). Conclusion Flexible analysis using the novel Amoy Myeloid Panel® method suggests that it can be used to assess the risk of relapse, evaluate the need for transplantation, and select optimal therapeutic agents. NGS-based mutation analysis provides useful information at any point in AML treatment and is expected to improve outcomes.

The Impact of ABO Incompatibility on the Outcomes of Hematopoietic Stem Cell Transplantation: A Single-Center Study From Pakistan.

Background and objective Allogeneic hematopoietic stem cell transplantation (alloHSCT) provides curative treatment for several hematological illnesses. In this study, we evaluated the impact ofABO compatibility and incompatibility onoutcomes and complications related to hematopoietic stem cell transplantation (HSCT) performed for various hematological disorders at our center. Methodology This was a retrospective, single-center, cohort study in which patients were categorized according to the ABO match and mismatch status. The mismatch group was further subcategorized into major, minor, and bidirectional groups. Results A total of 117 patients underwent alloHSCT, out of which 82 (70.1%) were male and 35 (30%) were female. The median age of the patients was 9.5 years (range: 46 years). The most common indications for stem cell transplant were beta-thalassemia major (BTM; n=58, 49%) and aplastic anemia (AA; n=42, 35.8%). However, the outcomes in match and mismatch groups showed significant results for positivedirect Coombs test (DCT), indicating the occurrence of hemolysis. Despite the increased need for blood transfusions, ABO blood group incompatibility (ABOi) had no negative impact on the clinical results. Conclusion Based on our findings, ABO incompatibility does not affect the outcomes in patients undergoing alloHSCT. Patient monitoring can aid in early detection and treatment, thereby minimizing the frequency of fatal events.

Improved Quality of Life of Patients With Sickle Cell Disease after Allogeneic Stem Cell Transplant: Another Indication for Transplant.

Sickle cell disease (SCD) is frequently inherited worldwide. The severity of SCD ranges from mild to severe, and the disease involves multiple complications, including pulmonary hypertension, stroke, recurrent vaso-occlusive crises, end-organ damage, and an increased mortality risk. Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative option for patients with SCD. The objective was to assess the quality of life of adolescent and adult patients with SCD receiving HCT pre-and post-transplant. An analytical cross-sectional study was conducted. Patients with SCD with at least one year of follow-up after HCT were interviewed to assess their quality of life pre-and post-transplant. This study was conducted at the Transplant Center of King Abdulaziz Medical City, Riyadh. The participants were identified through non-probability consecutive sampling. The FACT-G questionnaire was used to assess the quality of life domains. Thirty-one patients were included. The median age of the respondents was 32 ± 6.3 years, and 16 were male (51.6%). The most frequent indication for stem cell transplantation (58%) was a vaso-occlusive crisis. The mean FACT-G scores pre- and post-transplantation were 55.2 ± 18.17 and 91 ± 14.58, respectively. The mean number of annual ER visits was significantly reduced from 27.3 pre-transplant to 6.6 post-transplant (P-value = 0.006). Of the respondents, 51.6% experienced no severe complications post-transplantation, and most (93.5%) reported improved quality of life. HCT significantly improved the quality of life of adult patients with SCD, with improvements in most FACT-G score domains. Although it was not measured by the FACT-G, the frequency of ER visits and hospital admissions were reduced significantly post-transplant, reflecting an improvement in the quality of life and a reduction in the cost of therapy for patients with SCD.

Indications for Hematopoietic Stem Cell Transplantation in Patients with Waldenstrom's Macroglobulinemia: A Consensus Project of the EBMT Lymphoma Working Party (LWP)/ European Consortium for Waldenstrom's Macroglobulinemia (ECWM)/International Waldenstrom's Macroglobulinemia Foundation (IWMF)

Indications for Hematopoietic Stem Cell Transplantation in Patients with Waldenstrom's Macroglobulinemia: A Consensus Project of the EBMT Lymphoma Working Party (LWP)/ European Consortium for Waldenstrom's Macroglobulinemia (ECWM)/International Waldenstrom's Macroglobulinemia Foundation (IWMF)

Attempts to optimize postinduction treatment in childhood acute myeloid leukemia without core-binding factors: A report from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG).

We previously reported that risk-stratified therapy and intensive postremission chemotherapy (PRC) contributed to the improved survival of childhood acute myeloid leukemia (AML) in the AML99 study, which led us to consider a reduction in the number of PRC courses with more restrictive indications for stem cell transplantation (SCT) in the successor AML-05 study. We here report the outcome of AML patients without core-binding factor mutation (non-CBF AML) in the AML-05 study. Two-hundred eighty-nine children (age<18years old) with non-CBF AML were eligible. Patients with unfavorable cytogenetics and/or poor bone marrow response to the first induction course were candidates for SCT in the AML-05 study. After two courses of induction, a further three courses of PRC were given in AML-05, while four courses were given in the AML99 study. The 3-year event-free survival (EFS) rate in the AML-05 study (46.7%, 95% CI: 40.6-52.6%) was comparable to that of non-CBF AML in the AML99 study (51.5%, 95% CI: 42.7-59.6%) (P=.16). However, the 3-year overall survival (OS) rate in the AML-05 study (62.9%, 95% CI: 56.3-68.8%) was slightly lower than that in the AML99 study (71.6%, 95% CI: 63.2-78.5%) (P=.060), mainly due to decreased remission induction rate and increased nonrelapsed mortality. In conclusion, reductions in the number of PRC courses from four to three, together with repetitive cycles of high-dose cytarabine, were acceptable for non-CBF childhood AML.

Better Transplant Outcomes with Umbilical Cord Stem Cells in Patients with Dyskeratosis Congenita

Background:Dyskeratosis congenita (DKC) is a rare genetic bone marrow failure (BMF) syndrome of unknown etiology with a multisystem involvement and predisposition for cancer. It presents as a classic triad of dystrophic nails, oral leukoplakia and skin hyperpigmentation. Hematopoietic stem cell transplant (HSCT) has been tried as a treatment option but there is limited data on outcomes in these patients.Methods:As the disease is rare with high mortality, there have been no prospective studies. Retrospective database analysis is an effective means to evaluate outcomes in this patient population. Our study utilized Pediatric Health Information Systems (PHIS) database, which is an administrative quality-controlled database from 43 not-for-profit children's hospital, to analyze healthcare outcomes in pediatric patients with DKC. ICD-9 code 757.39 was used to identify the disease classification and as the only condition with an indication for stem cell transplant, we isolated the cases that underwent HSCT with that diagnostic code.Results: A total of 40 patients with DKC were identified who underwent transplant. A higher incidence was noted in Caucasian males with no significant difference in mortality across gender and ethnicity. The median length of hospitalization was 48 days (range 8.5 to 160.5 days) with a mean age of hospital admission at 93 months (95% CI: 70, 117). All the transplants were allogeneic with almost 20% umbilical cord (UCT) stem cell transplants. There was 15% mortality noted in this patient population, with all of deaths occurring prior to 2012. The complication rate (including acute and chronic GVHD as well as graft failure) was noted to be 37.5%, with acute GVHD being most common (20%). Fludarabine, Alemtuzumab, Cyclophosphamide, and Melphalan based conditioning regimen were most commonly used. Cyclosporine (65%), steroids (80%), Mycophenolate mofetil (50%) and Tacrolimus (40%) were commonly used for GVHD prophylaxis. Despite small numbers, significantly lower mortality was noted in UCT as compared to the other allogeneic stem cell transplants (p<0.01).Conclusion: Limited literature is available on pediatric transplant outcome data in DKC. UCT has better transplant outcomes in DKC patients due to longer telomere lengths of donor stem cells. Larger studies are needed for to compare transplant outcomes from different sources. DisclosuresNo relevant conflicts of interest to declare.

Risk-Adjusted Therapy of Acute Lymphoblastic Leukemia Can Optimize the Indication of Stem Cell Transplantation and Cranial Irradiation: Results of Japan Association Childhood Leukemia Study Group (JACLS) Protocol ALL-02

BACKGROUNDThe trial JACLS ALL-02 for treatment of childhood acute lymphoblastic leukemia (ALL) was designed to reduce acute and long-term toxicity in selected patient groups with favorable prognosis and to improve outcome in unfavorable-risk groups by treatment intensification. These aims were pursued through a refined stratification strategy using white blood cell count, age, immunophenotype, unfavorable genetic aberrations, and treatment response providing an excellent discrimination of risk groups. PATIENTS AND METHODSBetween April 2002 and March 2008, 1252 children with newly diagnosed de novo ALL with 1-18 years of age were enrolled to JACLS ALL-02 trial. Ph+ALL, mature B-ALL, and NK-leukemia were excluded. Patients with BCP-ALL were stratified into 3 groups: standard-risk (SR), high-risk (HR), extremely high-risk (ER), based on initial prednisolone (PSL) response and the modified National Cancer Institute(NCI) workshop criteria. Prednisolone poor response (PPR) was determined after 7 days of monotherapy with prednisone and one intrathecal dose of methotrexate. PSL good responders (PGR; < 1,000 blasts/microL) were divided into SR and HR according to the modified NCI workshop criteria by WBC 10K and age 10, and received conventional therapy. BCP-ALL with PPR (≥ 1,000 blasts/microL) or t(4;11), and acute mixed lineage leukemia/ acute unclassified leukemia were assigned to ER and received intensified post-induction therapy . Patients with T-ALL were treated by a specific protocol that was different from the protocol used for BCP-ALL. Bone marrow response was also evaluated in aspiration smears on day 15 and 33 of induction treatment, and those who had slow early bone marrow response, defined as an M3 marrow on day 15 or M2/3 marrow on day33, shifted to the higher risk and received augmented post-induction therapy. Cranial irradiation was restricted to patients with initial central nerve system involvement or T-ALL with high WBC (≥10K) at diagnosis. Alternatively, protracted TIT was given during induction, intensification and maintenance depending on the risk group (12 doses in SR/T and 15 in HR/ER). Slow early responders who had an M3 marrow on day 15 in ER/T or M2/3 marrow on day33 in any risk, underwent to stem cell transplantation (SCT). PPRs without slow early bone marrow response underwent to SCT only if a matched sibling donor was available. The probability of event-free survival (EFS) and overall survival were constructed using the Kaplan-Meier method. Events in the analysis of EFS included induction failure, death, relapse and secondary malignant neoplasm. All statistical analyses were done according to intent-to treat methods. RESULTSEstimated 4-year EFS and OS for all 1252 patients was 83.7% (SE=1.1) and 90.3% (SE=0.89), slightly better in EFS than the former study (ALL-97; 79.3%, SE=1.7, p=0.054). The SR group (N=457, 37%) achieved excellent 4-year EFS of 90.4% (95%CI: 87.2, 92.7) and 4-year OS 97.3% (95.3, 98.5); in SR without slow early bone marrow response, patients with hyperdiploid and triple trisomy showed excellent 4-year EFS/OS of 100%. In the HR group (N=542, 43%), the estimated 4-year EFS and 4-year OS were 84.9% (81.5, 87.7) and 89.3% (86.3, 91.6), respectively; older age (≥ 6 years) was predictive for inferior OS (hazard ratio=1.14, p<0.0001), and ETV6-RUNX1 was predictive for favorable OS (HR=0.182, p<0.03). In the ER group (N=139, 11%), intensification of consolidation treatment using high-dose dexamethasone and AML-oriented agents led to considerable improvement yielding a 4-year EFS of 74.1% (66.0, 80.6) and a 4-year OS of 87.0 (80.2, 91.6). In T group (N=107, 8%), the dose reduction of L-asparaginase and anthracyclines compared with the ALL-97 resulted in inferior outcome in 4-year EFS 65.1% (54.9, 73.6), but not in 4-year OS 83.2% (74.6, 89.1), although the incidence of pancreatitis decreased. In non-T-ALL, The 5-year cumulative risk of an isolated and total CNS relapse was lower in ALL-02 than in ALL-97 (isolated CNS relapse: 0.8% vs 2.7%, p=0.017, total CNS relapse: 1.4% vs 4.5%, p=0.01). The proportion of CRT and SCT were 2%, 8% in ALL-02 respectively, whereas 31%, 11% in ALL-97 respectively. CONCLUSIONSRefined stratification and risk-adjusted therapy in the JACLS ALL-02 trial can bring about the abolition of prophylactic CRT in non-T ALL and the optimized indication of SCT without compromising the treatment results. DisclosuresNo relevant conflicts of interest to declare.

Strategies for reducing the treatment‐related physical burden of childhood acute myeloid leukaemia – a review

Over the last four decades the survival of paediatric patients with acute myeloid leukaemia has gradually increased to 70% in high-income countries. The therapy is very intensive and associated with many acute and long-term side effects. The early death rate has been reduced to 1-4%. The acute toxicity is a limiting factor for improving survival in low-income countries. Transplant is associated with more endocrinological late effects while cardiotoxicity is more common after relapse. Reducing the physical costs of therapy without jeopardizing survival may be accomplished by optimal supportive care, less cardiotoxic anthracyclines, less consolidation courses and strict indications for stem cell transplantation. Analysing scenarios with different frequency of transplantation in first complete remission show similar overall survival rates, indicating that almost all patients can be spared the procedure in first remission. Reducing relapse risk is an effective way of reducing toxicity and more targeted therapy and improved risk group stratifications are needed.

Editorial: Current Challenges in Immune and Other Acquired Cytopenias of Childhood.

Editorial: Current Challenges in Immune and Other Acquired Cytopenias of Childhood.

Role of HRCT Chest in Post Stem Cell Transplant Recipients Suspected of Pulmonary Complications.

Stem cell transplantation is today's procedure of choice for management of various hematopoietic malignant and severe immunogenic disorders. High Resolution Computed Tomography (HRCT) is a common technique for the diagnosis of pulmonary complications in stem cell transplant recipients. There are a large number of complications which can complicate the post-transplant period. To study the role of HRCT chest in stem cell transplant patients developing pulmonary complications, detect any evidence of infection, detect clinical signs of lung infections, Graft versus Host Disease (GvHD) or other regimen related toxicities outlined earlier, detect any evidence of GvHD and correlate these clinical signs with radiological changes in the lungs. The study was a prospective study of 52 participants with indication of stem cell transplantation. The study included recipients of HSCT transplant and the exclusion criteria was patients who failed for engraftment and having an associated history of pulmonary embolism. Patients were screened for pre-transplant chemotherapy, clinical examination, laboratory investigations including blood and biochemical examinations, imaging by ultrasound, chest radiography, baseline HRCT and a follow-up for post-transplant infections and complications with 16 slice Siemens CT scan. Statistical analysis was done using Pearson's chi-squared test. Four patients among the total 56 were excluded due to non-engraftment. The most common associated findings in decreasing order are (these patients died): consolidation, pancytopenia and gastrointestinal tract symptoms with VOD (Veno-Occlusive Disease). These findings were seen on HRCT as consolidation, cavities, ground glass opacities, fibrotic changes, bronchiectatic changes and tree in bud appearance. The study highlights the significant positive findings on the HRCT which were missed on routine chest radiograph and can be used for early diagnoses. Thus, HRCT helped in decreasing the mortality. The abnormal vitals and TLC counts showed a significant relation between the numbers of death in the study.

Childhood relapsed acute lymphoblastic leukemia: Biology and recent treatment progress.

Acute lymphoblastic leukemia (ALL) is the most frequent cancer in children. Despite remarkable improvement in the prognosis of childhood ALL over the past few decades, the treatment of relapsed ALL is still challenging. The prognosis of first ALL relapse is associated with time of relapse after initial therapy, sites of relapse, and immunophenotype. More recently, response to treatment, which is evaluated by assessment of minimal residual disease (MRD), has been found to be clinically significant in relapsed ALL as well as in the initially diagnosed disease. Utilizing these factors, risk-oriented treatment stratification for first ALL relapse has been established. In the standard-risk group for first ALL relapse, intensification of conventional ALL-type therapy can provide a cure in approximately 70% of patients. It is important to assess MRD after reinduction therapy to determine the indications for stem cell transplantation in the standard-risk group. In contrast, no standardized therapy has been established for the high-risk group, which accounts for more than half of relapsed ALL patients. Recent studies have shed light on the clonal origin of relapsed ALL, which usually exists as a minor subclone at the time of initial diagnosis. Clonal selection and evolution take place during chemotherapy, resulting in distinct genetic and epigenetic characteristics of relapsed ALL, some of which are linked to drug resistance, a common and problematic feature of ALL after relapse. To overcome resistance to standard ALL-type therapy, and considering the heterogeneous biological background of high-risk relapsed ALL, innovative therapies using new agents are necessary.

Akut Myeloblastik Lösemili Çocuklarda Kök Hücre Nakli

In patients with acute myeloblastic leukemia, according to the European bone marrow transplant handbook, the indications for stem cell transplantation, conditioning regimen, donor selection and information about sources of stem cells will be evaluated.

A Limited But Necessary Indication of Stem Cell Transplantation for Chronic Myelogeneous Leukemia in the Era of Tyrosine Kinase Inhibitors

A Limited But Necessary Indication of Stem Cell Transplantation for Chronic Myelogeneous Leukemia in the Era of Tyrosine Kinase Inhibitors

Phase I Study of Eltrombopag for Promoting Thrombopoiesis in Patients Undergoing Stem Cell Transplantation After Total Body Irradiation

AbstractAbstract 219 Purpose:Prolonged intervals of thrombocytopenia are common after stem cell transplantation, and platelet transfusions are the only temporary therapy before engraftment. Risk of thrombocytopenia is greater in patients receiving total body irradiation (TBI) in their conditioning regimen. Eltrombopag is a small-molecule, nonpeptide oral agent that functions as an agonist of the thrombopoietin receptor. It is approved by the FDA for the treatment of chronic idiopathic thrombocytopenic purpura and is being developed as a treatment for thrombocytopenia of other various etiologies. We report updated results of a Phase I clinical trial assessing the safety, pharmacokinetics (PK) and maximum tolerated dose (MTD) of once daily oral eltrombopag in patients undergoing stem cell transplantation with a conditioning regimen containing TBI ≥ 400 cGy. Methods:A Phase I dose-escalation clinical trial was conducted to evaluate the safety and PK of eltrombopag at 4 different dose levels: 75, 150, 225, and 300 mg given once daily for 27 days, starting 24–48 hours post stem cell transplantation to eligible patients ≥18 years old. Patients with various indications for stem cell transplantation, KPS ≥70%, and TBI ≥ 400 cGy were eligible. Patients receiving either an autologous (Auto) or allogeneic (Allo) stem cell transplantation from a sibling, related donor, or matched unrelated donor (MUD) were eligible. Stem cells from peripheral blood (PBSC) or bone marrow were permitted; however, cord blood stem cell transplantation was not permitted. Patients at risk of thromboembolism or with a history of thromboembolic disease in the preceding 6 months were excluded. PK sampling was obtained over a 24 hour period after the first dose of eltrombopag as well as during the second week of treatment (steady-state). Results:As of August 1 2012, a total of 19 subjects (7 AML, 4 lymphoma, 1 CML, 1 MDS, 1 myelofibrosis, 2 ALL, 1 APML, 1 Biphenotypic Leukemia and 1 CLL/SLL) were enrolled, and 15 completed protocol treatments. All 19 were PBSC transplants with 12 MUD, 6 Allo and 1 Auto. Three subjects were completed at each dose level up to 225 mg with six completing treatment at the highest dose of 300mg. Four subjects were replaced because drug compliance was less than 75%. To date, 11/19 are alive while 8/19 have died (3 related to graft vs. host disease (GVHD), 3 Infection-related and 2 related to disease progression (f/u interval: 5.7 – 30 months). No dose limiting toxicities (DLTs) have been observed. The most common adverse events (AEs) up to the 300 mg dose level were related to standard stem cell transplantation, which included low blood counts, fatigue, headache, diarrhea, nausea, peripheral edema, hypoalbuminemia, hyperglycemia, hypocalcemia, and hypomagnesemia. Possibly drug-related AEs were dry skin, rash, elevated creatinine, and hypokalemia; these were all grade 3 or less. There were 12 severe AEs observed in 8 subjects, which included infection (3/19), pulmonary embolism (PE) (1/19), acute renal failure (3/19), gastrointestinal (2/19), acute respiratory distress syndrome (1/19), pericarditis (1/19) and GvHD skin rash (1/19). Most SAEs were considered related to stem cell transplant, except one subject at 75 mg with PE possibly related to eltrombopag, but also possibly related to stem cell transplant and cancer diagnosis. The PE occurred 9 days after stopping eltrombopag at which time platelet count was 252K. Time to platelet engraftment and number of platelet transfusions were also documented for each enrolled patient. Median time to platelet engraftment for all subjects on this study was 16 days. PK data are summarized in Table 1 and Figure 1. A dose-dependent increase in plasma exposure of eltrombopag was observed; although some saturation of absorption is evident at the 300 mg dose level. (Figure 1). Conclusions:27-day once daily dosing of eltrombopag to enhance platelet recovery for post-transplant thrombocytopenia is well tolerated, with no DLTs observed up to the 300 mg dose level. Most AEs were transplant related. PK showed proportional plasma concentration up to 225 mg daily dosing, with some saturation of drug absorption above 225 mg. [Display omitted] [Display omitted] Disclosures:Liesveld:Eisai: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Ariad: Honoraria. Off Label Use: Eltrombopag not approved post-transplant. Dawson:GlaxoSmithKline: Employment.

Attempts to Optimize Post-Induction Treatment in Childhood Acute Myeloid Leukemia without Core Binding Factors: A Report From the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG)

AbstractAbstract ▪3545▪This icon denotes a clinically relevant abstract Background:With intensive chemotherapy and optimal risk stratification, 80–90 % of children with acute myeloid leukemia (AML) achieve complete remission (CR) which translates into a long-term disease-free survival in as many as 50–60% of patients. We have previously reported that risk stratified therapy and intensive use of cytarabine improved the outcome of childhood AML in AML99 study with 5-year event free survival (EFS) of 61.6% and 5-year overall survival (OS) of 75.6% (Tsukimoto I. J Clin Oncol 2009;27:4007–13), which gave us an additional impetus to reduce the number of consolidation courses with more restrictive indication for stem cell transplantation (SCT). We here report the outcome of successor nation-wide multi-institutional study AML-05, focusing on the AML patients without core binding factor (CBF). Patients & Methods:47 eligible children (age <18 years) with de novo AML (acute promyelocytic leukemia and Down syndrome patients were excluded). Three patients were excluded from the efficacy analyses: one protocol violation, 1 changing to non-JPLSG member hospital at the patient’s request, and 1 withdrawal of the JPLSG institutional membership. After 2 courses of common induction therapies, patients were stratified by the specific cytogenetic characters and morphological treatment response into 3 risk groups. Low risk (LR) children were defined as those with t(8;21) or inv(16), and good bone marrow response (BMR) to the first induction course. High risk (HR) children were those with abnormalities of monosomy 7, 5q-, t(16;21)(p11;q22), t(9;22), FLT3-ITD, and/or poor BMR to the first induction course. Intermediate risk (IR) children were those who were neither LR or HR group. Only patients assigned to HR were candidate for SCT in first CR in AML-05, whereas patients with IR were also allocated to SCT, if HLA-matched siblings were available in the former AML99. Patients with CR after two courses of induction therapy further received 3 courses of consolidation chemotherapy in AML-05; whereas 4 courses of consolidation therapy were given in AML99. The total cumulative dose of anthracyclines, Mitoxantrone and Idarubicin, was 375 mg/m2 in the IR/HR chemotherapy both in AML-05 and AML99. Conversion rate of 5:1 was used to compare the cumulative dose of Daunorubicin and Mitoxantrone/Idarubicin. Results:Three-year EFS and 3y-OS of all 444 patients was 55.3% (95%CI, 50.2 – 60.1%) and 73.2% (68.3 – 77.5%), respectively. The median follow-up period for living patients was 3.1 years (range, 0.8 – 5.4 years). Two hundred eighty-nine non-CBF-AML patients [t(9;11), N=39 (13.5%); 11q23, N=27 (9.3%); Normal, N=81 (28.0%); Others, N=137 (47.4%)] in the AML-05 and 151 patients [t(9;11), N=15 (9.9%); 11q23, N=26 (17.2%); Normal, N=53 (35.1%); Others, N=55 (36.4%)] in AML99 were compared. There were no significant differences in basic characteristics such as sex and age/WBC at diagnosis. Incidence of FLT3-ITD in AML-05 cohort were identical to that in AML99 [AML-05 cohort, N= 42/289 (14.5%); AML99, N= 15/82 (18.2%), p=0.41]. CR rate in AML-05 was inferior to that in AML99 (81.0% vs. 90.7%, p = 0.008). There was no significant differences in 3y-EFS of non-CBF AML among 2 cohort [47.5% in AML-05 (95%CI, 41.2– 53.6%) vs. 49.7% in AML99 (41.5 – 57.3%), p= 0.43], however, there was a tendency of lower 3y-OS among them [62.8% in AML-05 (95%CI, 56.2– 68.7%) vs. 70.9% in AML99 (62.9 – 77.4%), p = 0.083]. The early death within 42 days in AML-05 (2.1%) were equivalent to that of AML99 (2.0%), whereas non-relapsed mortality were significantly increased in AML-05 compared with that of AML99 [44/289 (15.2%) in AML-05; 11/151 (7.3%) in AML99, p=0.022], which was due to increased mortality among infants. SCT rate in the 1stCR was lower in the non-CBF AML-05 compared with that in AML99 [47/289 (16.3%) in AML-05; 40/151 (26.4%) in AML99, p=0.011]. Conclusions:Reduction on consolidation chemotherapy courses from four to three, together with incorporation of repetitive cycles of high-dose cytarabine were adequate for non-CBF childhood AML, and did not compromise the treatment results in AML-05 despite of adaptation of more restrictive indication for SCT in 1st CR. Non-CBF-AML is a cytogenetically heterogeneous disease, hence the mechanism underlying these prognostic differences should be studied. Disclosures:No relevant conflicts of interest to declare.

Phase I Study of Eltrombopag for Promoting Thrombopoiesis in Patients Undergoing Stem Cell Transplantation After Total Body Irradiation,

Abstract 3295▪▪This icon denotes a clinically relevant abstract Purpose:Prolonged intervals of thrombocytopenia are common after hematopoietic stem cell transplantation (HSCT), and platelet transfusions are the only effective therapy. Risk of thrombocytopenia is greater in patients (pts) receiving total body irradiation (TBI) in their conditioning regimen. Eltrombopag (ePag) is a small-molecule, nonpeptide oral agent that functions as an agonist of the thrombopoietin receptor. It is approved by FDA for the treatment of chronic ITP and is being developed as a treatment for thrombocytopenia of other various etiologies. We report results of an ongoing Phase I clinical trial assessing the safety, pharmacokinetics (PK) and maximum tolerated dose (MTD) of once daily oral ePag in pts undergoing HSCT with a conditioning regimen containing TBI ≥ 400 cGy. Methods:A Phase I dose-escalation clinical trial was conducted to evaluate the safety and PK of ePag at 4 different dose levels: 75, 150, 225, and 300 mg, once daily for 27 days, starting 24–48 hours post HSCT to eligible pts ≥18 yrs old. Pts with various indications for stem cell transplantation, KPS ≥70%, and TBI ≥ 400 cGy were eligible. Pts receiving either an autologous (Auto) or allogeneic (Allo) HSCT from a sibling, related donor, or matched unrelated donor (MUD) were eligible. Stem cells from peripheral blood (PBSC) or bone marrow were permitted; however, cord blood transplant was not permitted. Pts at risk of thromboembolism, or with a history of thromboembolic disease in the preceding 6 months, were excluded. PK sampling was obtained over a 24 h period after the first dose of ePag, as well as during the second week of treatment (steady-state). Results:As of July 1 2011, a total of 10 subjects (4 AML, 2 lymphoma, 1 CML, 1 MDS, 1 myelofibrosis, and 1 CLL/SLL) were enrolled, and 9 completed protocol treatments. All 9 were PBSC transplants with 6 MUD, 2 Allo and 1 Auto. Three subjects were completed at each dose level up to 225 mg. Enrollment is continuing at the 300 mg dose level. To date, 6/9 are alive while 3/9 died of non-relapse related causes (CMV pneumonitis and respiratory failure in 1, and steroid refractory GI GvHD in 2, f/u interval: 4.4 – 6.9 mo). No dose limiting toxicities (DLTs) have been observed. Most common adverse events up to 225 mg dose level were related to standard stem cell transplantation, which included low blood counts, fatigue, headache, diarrhea, nausea, peripheral edema, hypoalbuminemia, hyperglycemia, hypocalcemia, and hypomagnesemia. There were 9 SAEs observed in 5 pts, which included infection (3/9), pulmonary embolism (PE) (1/9), acute renal failure (2/9), gastrointestinal (2/9), and ARDS (1/9). Most SAEs were considered unrelated or unlikely related to ePag treatment except for the PE, which was considered possibly related to ePag but not considered a DLT. This subject had other risk factors for PE and the PE occurred 9 days after ePag had stopped at a platelet count of 252K. Time to platelet engraftment and number of platelet transfusions were documented for each enrolled pt. PK sampling demonstrated a dose dependent increase in plasma concentration of ePag (Figure 1). PK parameters for the 75, 150, and 225 mg dose levels are summarized in Table 1. [Display omitted] Table 1:Summary plasma PK parameters for 75, 150, and 225 mg dose levels from ELT112549aDose (mg)Ntmax (h)Cmax (μg/mL)AUC(0-τ) (μg.h/mL)Day 2Week 2Day 2Week 2Day 2Week 27534.07 (4.00, 6.00)4.00 (2.08, 6.33)4.57 (13)9.23 (37)48.9 (21)123 (24)15032.08 (2.00, 4.25)2.00 (1.00, 4.00)8.02 (35)15.6 (28)88.6 (18)253 (19)22534.00 (2.25, 4.32)2.00 (1.92, 4.08)18.7 (66)25.2 (65)190 (55)340 (76)aGeometric mean (CV%), except for tmax, median (minimum, maximum) Conclusions:27-day once daily dosing of ePag to enhance platelet recovery for post-transplant thrombocytopenia is well tolerated, with no DLTs observed up to the 225 mg dose level to date. Most AEs were transplant related. PK and the plasma exposure of ePag appears dose proportional over the studied dose range after single-dose and steady-state administration. Once-daily administration of up to 225 mg ePag for the transplant population receiving TBI ≥ 400 cGy as part of the conditioning regimen appears to be safe and well tolerated. Acknowledgment:The study is supported by Biomedical Advanced Research and Development Agency (BARDA), and by GlaxoSmithKline who also provided the study drug. Disclosures:Off Label Use: Promacta (eltrombopag) is an oral TPO Receptor agonist approved for the treatment of chronic ITP. The study being reported in this abstract is a phase I MTD study to evaluate eltrombopag for promoting thrombopoiesis in patients undergoing Stem Cell Transplantation after Total Body Irradiation. Dawson:GlaxoSmithKline: Employment.

Improved Survival using Dual Monoclonal Antibody Therapy with Aggressive Anti-Microbial Prophylaxis In Steroid-Refractory Acute Graft-Versus-Host Disease

AbstractAbstract 1262Steroid-refractory acute graft versus host disease (aGVHD) is associated with a poor prognosis. Although clinical responses occur to second line therapy they are associated with high rates of infection and dismal long-term survival. Blockade at 2 different points in the cytokine cascade with infliximab and daclizumab (double antibody therapy, DAT), along with aggressive infection prophylaxis may improve outcomes. We retrospectively reviewed our experience using DAT in steroid-refractory aGVHD. Between December 2005 and December 2009, 22 patients were treated of which 20 are evaluable. All patients had persistent or progressive aGVHD despite 1–2 mg/kg/d steroids for a median of 9 days (range 2–55). Five patients had failed 2nd line systemic aGVHD therapy and 1 patient failed 3rd line therapy prior to DAT. Combination therapy was given for aGVHD grade 2 (n=3), 3 (n=13), or 4 (n=4). GVHD involved the skin in 7 patients, the liver in 9 patients and GI tract in 16 patients. The median age at time of therapy was 55 years (range 29–69). Grafts were from HLA identical siblings (9), 10 locus matched unrelated donors (5), 9/10 locus matched unrelated donors (3), cord blood (2) or 5/10 haploidentical donor (1). The conditioning regimen was myeloablative in 10 patients, and either nonmyeloablative or reduced intensity in 10 patients. Indications for stem cell transplant were acute leukemia (7), chronic myelogenous leukemia (2), chronic lymphocytic leukemia (1), myelodysplastic syndrome (4), non-Hodgkins lymphoma (5), and multiple myeloma (1). Most patients received methotrexate (MTX) with tacrolimus (FK)(14) or mycophenolate (MMF) (4) for GVHD prophylaxis; one patient received MTX with FK and MMF and one FK alone. Fifteen patients developed aGVHD after the primary transplant and five after donor lymphocyte infusion. Daclizumab was given (1mg/kg) day 1,4,8,15, and 22, and infliximab (10mg/kg) days 1,8,15, and 22. Steroid therapy was aggressively tapered upon commencement of DAT. Maximal response achieved by day 60 post initiation of therapy was assessed. Five pts (25%) attained a CR (resolution of all symptoms), 10 (50%) PR (improvement in ≥ 1 organ & no progression in others), 2(10%) MR (improvement in ≥ 1 organ & deterioration or new symptoms in others) and 3 (15%) no response. Five patients received 1–2 additional courses of DAT at a median of 60 days. Three patients (15%) were concurrently on an investigational protocol utilizing mesenchymal stem cells. All patients received antifungal (azole with mold coverage or echinocandin), anti-Herpes virus, and Pneumocystis prophylaxis. Patients with gastrointestinal GVHD also received antibacterial prophylaxis irrespective of neutropenia. Patients were monitored once or twice weekly for CMV reactivation and received preemptive therapy upon reactivation. Only two patients had documented fungal infections: Mucormycosis in 1 and Candida parapsilosis in 1. Sixteen (80%) of patients had bacterial infections, including 21 gram-positive infections and 13 gram-negative infections. Viral infections, primarily CMV reactivation, occurred in 16 patients (80%). As of August 2010, 12 patients have died after a median of 102 days from initiation of DAT (range 14–658) (5 from relapsed or progressive disease, 3 from aGVHD, 2 from cGVHD, and 2 from organ failure). With a median follow up of 511 days for living patients, the estimated probability of survival at 6 months and 12 months is 55% and 50%, respectively. DAT is an effective therapy for steroid-refractory aGVHD. Survival beyond 6 months can be achieved in approximately half the patients using this strategy. Aggressive antifungal and antiviral prophylaxis may have contributed to this outcome. Disclosures:Off Label Use: Infliximab and daclizumab are not FDA approved for GVHD.

Prognostic implications of mutations and expression of the Wilms tumor 1 (WT1) gene in adult acute T-lymphoblastic leukemia

The role of the Wilms tumor 1 gene (WT1) in acute leukemias has been underscored by mutations found in acute myeloid leukemia identifying patients with inferior survival. Furthermore, aberrant expression of WT1 in acute myeloid leukemia was associated with an increased risk of relapse. No larger studies have performed a combined approach including WT1 mutation and expression analyses in acute T-lymphoblastic leukemia. We analyzed the WT1 mutations and the expression status in a total of 252 consecutive adult patients with newly diagnosed T-lymphoblastic leukemia, who were registered on the GMALL 06/99 and 07/03 protocols and had sufficient material available. The GMALL protocols included intensive chemotherapy as well as stem cell transplantation according to a risk-based model with indication for stem cell transplantation in first complete remission for early and mature T-lymphoblastic leukemia patients; patients with thymic T-lymphoblastic leukemia were allocated to a standard risk group and treated with intensive chemotherapy. Twenty of the 238 patients analyzed had WT1 mutations (WT1mut) in exon 7. WT1mut cases were characterized by immature features such as an early immunophenotype and higher WT1 expression. In thymic T-lymphoblastic leukemia, WT1mut patients had an inferior relapse-free survival compared to WT1 wild-type patients. T-lymphoblastic leukemia patients with aberrant WT1 expression (high or negative) showed a higher relapse rate and an inferior outcome compared to patients with intermediate WT1 expression. In the standard risk group of thymic T-lymphoblastic leukemia, aberrant WT1 expression was predictive for an inferior relapse-free survival as compared to patients with intermediate expression. In multivariate analysis, WT1 expression was of independent prognostic significance for relapse-free survival. WT1 mutations were associated with an inferior relapse-free survival in standard risk thymic T-lymphoblastic leukemia patients. Moreover, altered expression associated with inferior outcome also suggests a role of WT1 in T-lymphoblastic leukemia and the potential use of molecularly-based treatment stratification to improve outcome.

Combination Daclizumab and Infliximab for Steroid Refractory Acute Graft-Versus-Host Disease.

Abstract 4643Systemic steroids are the mainstay of therapy for GVHD, but treatment failure is common. Inflammatory cytokines, including IL-2 and TNF-a, are important mediators of GVHD, and may be critical targets for therapy. Given the ineffective treatment options for patients (pts) with steroid-refractory GVHD (SR-GVHD) and the almost universally poor outcomes with available therapies, between June 2001-May 2008, we treated 22 patients with SR-GVHD with a combination of anti-cytokine therapy that included daclizumab and infliximab. Seventeen of these patients were evaluable for a retrospective review of detailed outcomes.The median age was 48 years (range 35-63) and grafts were from HLA matched siblings (5), matched unrelated donors (9), 1 antigen mismatched unrelated donors (2), or cord blood (1). Indications for stem cell transplant (SCT) were acute leukemia (9), chronic myelogenous leukemia (1), lymphoma (5) chronic lymphocytic leukemia (1) and multiple myeloma (1). Most patients received methotrexate with either tacrolimus (14) or cyclosporine (CSA) (2) and 1 patient received CSA with steroids as initial GVHD prophylaxis. High dose steroids were started for acute GVHD a median of 39 days after transplant in 12 pts (range 25-119). Five additional patients developed SR-GVHD a median of 46 days (range 25-119) after donor lymphocyte infusion.All patients had persistent or progressive acute GVHD despite 1mg/kg/day (4 pts) or 2 mg/kg/day (13 pts) of corticosteroids for a median of 8 days (range 5-26) and were treated for acute GVHD severity index B (3), C (10) or D (4). GVHD involved the skin in 9 pts, liver in 9 pts, and gut in 15 pts. Daclizumab was given at 1.5 mg/kg day 1 and 1 mg/kg day 4, 8, 15, and 22. Infliximab was given at 10 mg/kg day 1,8,15, and 22. Overall, 47% of patients responded to therapy. Four patients (24%) had complete resolution of symptoms and 4 (24%) had partial responses. The remaining 9 patients failed to respond, progressed or had a mixed response. Additional therapies were started in 7 patients. Similar to other available reports on SR-GVHD, survival was limited and all pts died at a median of 6.7 months (range 1.6-26) from transplant and 37 days from initiation of daclizumab/ infliximab (8 from infection, 5 from GVHD, 2 from relapsed disease, and 2 from other causes). Data from additional patients will be presented. Although this is a retrospective analysis, these results suggest that combination anti-cytokine therapy with daclizumab/infliximab has significant activity in SR-GVHD, but outcomes remain poor. New methods to prevent and treat GVHD are urgently needed. Disclosures:Off Label Use: Daclizumab and Infliximab were used to treat acute Graft versus Host Disease. Porter:Genentec: Spouse employed by Genentech, owned by Roche, manufacturer of daclizumab.

Criteria for the selection of radiation accident victims for stem cell transplantation.

The management of acute radiation syndrome in persons inadvertently exposed to total-body irradiation greatly benefits from the experience gained in previous clinical management situations. Within the framework of exposure to high doses, one of the most critical issues is the question of whether hematopoietic stem cell transplantation is indicated. A valid answer can be given with appropriate accuracy based on a thorough analysis and evaluation of all accessible case histories. Based on the clinical evaluation of patients severely affected with acute radiation syndrome, the following recommendations may be issued. There is limited indication for stem cell transplantation when there is accompanying severe radiation damage to organ systems other than the hematopoietic system. The optimum duration of pancytopenia can be estimated using the biomathematical model introduced in this article.