Impact of Conditioning Regimen on Outcomes for Children with Acute Myeloid Leukemia Undergoing Transplantation in First Complete Remission. An Analysis on Behalf of the Pediatric Disease Working Party of the European Group for Blood and Marrow Transplantation.

Hematopoietic stem cell transplantation (HSCT) represents the cornerstone of treatment in pediatric high-risk and relapsed acute myeloid leukemia (AML). The aim of the present study was to compare outcomes of pediatric patients with AML undergoing HSCT using 3 different conditioning regimens: total body irradiation (TBI) and cyclophosphamide (Cy); busulfan (Bu) and Cy; or Bu, Cy, and melphalan (Mel). In this retrospective study, registry data for patients > 2 and <18 years age undergoing matched allogeneic HSCT for AML in first complete remission (CR1) in 204 European Group for Blood and Marrow Transplantation centers between 2000 and 2010 were analyzed. Data were available for 631 patients; 458 patients received stem cells from a matched sibling donor and 173 from a matched unrelated donor. For 440 patients, bone marrow was used as stem cell source, and 191 patients received peripheral blood stem cells. One hundred nine patients received TBICy, 389 received BuCy, and 133 received BuCyMel as their preparatory regimen. Median follow-up was 55 months. Patients receiving BuCyMel showed a lower incidence of relapse at 5 years (14.7% versus 31.5% in BuCy versus 30% in TBICy, P < .01) and higher overall survival (OS) (76.6% versus 64% versus 64.5%, P = .04) and leukemia-free survival (LFS) (74.5% versus 58% versus 61.9%, P < .01), with a comparable nonrelapse mortality (NRM) (10.8% versus 10.5% versus 8.1%, P = .79). Acute graft-versus-host disease (GVHD) grades III and IV but not chronic GVHD, was higher in patients receiving BuCyMel. Older age at HSCT had an adverse impact on NRM and the use of peripheral blood as stem cell source was associated with increased chronic GVHD and NRM as well as lower LFS and OS. Among pediatric patients receiving HSCT for AML in CR1, the use of BuCyMel conditioning proved superior to TBICy and BuCy in reducing relapse and improving LFS.

Hematopoietic stem cell transplantation in the Eastern Mediterranean Region (EMRO) 2011-2012: A comprehensive report on behalf of the Eastern Mediterranean Blood and Marrow Transplantation group (EMBMT).

OBJECTIVE/BACKGROUND: The Eastern Mediterranean Blood and Marrow Transplantation (EMBMT) group has accumulated over 31 years of data and experience in hematopoietic stem cell transplantation (HSCT), particularly in hemoglobinopathies, severe aplastic anemia, inherited metabolic and immune disorders, in addition to a wide array of hematologic malignancies unique to this region. A regional update in current HSCT trends is highly warranted. We studied the trends of HSCT activities in World Health Organization-Eastern Mediterranean (EMRO) region, surveyed by the EMBMT, between 2011 and 2012. METHODS: Retrospective analysis of the survey data mainly of cumulative number of transplants, types of transplants (autologous vs. allogeneic), types of conditioning such as myeloablative versus reduced intensity was conducted. Also, trends in leukemias, hemoglobinopathies, severe aplastic anemia, inherited bone marrow failure syndromes, amongst others were analyzed. RESULTS: Twenty-one teams from nine EMRO countries reported their data (100% return rate) to the EMBMT for the years 2011-2012, with a total of 3,546 first HSCT (1,670 in 2011; 1,876 in 2012). Allogeneic HSCT (allo-HSCT) represented the majority (62%) in both years. The main indications for allo-HSCT were acute leukemias (988; 46%), bone marrow failure syndromes (421, 20%), hemoglobinopathies (242; 11%), and immune deficiencies (157; 7%). There was a progressive increase in the proportions of chronic myeloid leukemia cases transplanted beyond first chronic phase (37 [7%] of all chronic myeloid leukemia cases in 2011 vs. 39 [29%] in 2012). The main indications for autologous transplants were multiple myeloma/plasma cell disorders (510; 39%), Hodgkin lymphoma (311; 24%), non-Hodgkin lymphoma (259; 20%), and solid tumors (163; 12%). Reduced intensity conditioning continued to show a progressive decrease over years (9.5% in 2011 vs. 7.9% in 2012), yet remained relatively low compared with contemporary practices in Europe published by EBMT. The vast majority (91%) of allo-HSCT source was from sibling donors with continued dominance of peripheral blood (64%) followed by bone marrow (33%).While umbilical cord blood transplants increased to 4% of allo-HSCT, matched unrelated donor remained underutilized and there was no haplo-identical transplant reported. Large centers with >50 HSCT/year, showed a continued increase in the total number of allo-HSCT over the past 2years that may be related to capacity building issues and require further studies. CONCLUSION: There is a discernable increase of HSCT rate in the EMRO region with a significant expansion in utilization of cord blood transplants and allogeneic peripheral blood-HSCT as a valuable source. However, further research of outcome data and the development of regional donor banks (cord blood and matched unrelated donors) may help to facilitate future planning to satisfy the escalating regional needs and augment collaboration within the EMBMT and globally.

Cytomegalovirus Reactivation in Adult Recipients of Autologous Stem Cell Transplantation: a Single Center Experience.

INTRODUCTION: Cytomegalovirus (CMV) reactivation and infection are well-recognized complications after allogeneic stem cell transplantation (SCT). Only a few studies have addressed CMV reactivation after autologous SCT (ASCT). METHODS: We retrospectively reviewed medical records of 210 adult patients who underwent ASCT for lymphoma or multiple myeloma (MM) at a single center from January 1(st), 2007 until December 31(st), 2012. All patients were monitored weekly with CMV antigenemia test till day 42 after transplantation, and for 2 months after last positive test in those who had any positive CMV antigenemia test before day 42. RESULTS: Thirty-seven (17.6%) patients had CMV reactivation; 23 patients had lymphoma while 14 had MM as the underlying disease. There was no difference in the rate of CMV reactivation between lymphoma and MM patients (20% versus 14.7%, P = 0.32). The majority of the patients were treated with ganciclovir/valganciclovir, all patients had their reactivation resolved with therapy, and none developed symptomatic CMV infection. None of the patients who died within 100 days of transplantation had CMV reactivation. Log-rank test showed that CMV reactivation had no effect on the overall survival of patients (P values, 0.29). CONCLUSION: In our cohort, CMV reactivation rate after ASCT was 17.6%. There was no difference in reactivation rates between lymphoma and MM patients. With the use of preemptive therapy, symptomatic CMV infection was not documented in any patient in our cohort. CMV reactivation had no impact on patients' survival post ASCT.

GCSF with or without chemotherapy compared to Plerixafor with GCSF as salvage mobilization regimen in patients with multiple myeloma and lymphoma: collection effectiveness and cost effectiveness analysis.

INTRODUCTION: Plerixafor is a novel mobilizing agent of peripheral blood stem cells (PBSCs) in lymphoma and multiple myeloma (MM) patients whose cells mobilize poorly. Due to the substantial cost associated with its use, we aimed to compare the effectiveness and cost effectiveness of Plerixafor + GCSF (PG) versus GCSF ± Chemotherapy (GC) as salvage mobilization regimens. METHODS: The charts of consecutive lymphoma and MM patients who had undergone at least one previous attempt of PBSCs mobilization that failed or resulted in an insufficient cell dose for transplant between 2007 and 2010 were retrospectively reviewed. Patients identified received salvage mobilization with GC (prior to 2009) or PG after Plerixafor's FDA approval. Data collected included demographics, medical histories, apheresis yields and transplant outcome. The cost effectiveness analysis was from the perspective of the Jordanian Ministry of Health. The incremental cost effectiveness ratio (ICER) was calculated by dividing the difference in cost by the difference in effectiveness for the two regimens. RESULTS: Five patients received GC and twelve received PG. A minimum CD34+ cell dose of 2 × 10(6) cells/kg was collected from 8 patients (67%) in the PG group compared to 3 (60%) in the GC group (p=0.79). The average costs were US$8570 and US$25,700 for the GC group and the PG group, respectively. The ICER was US$244,714 per successful stem cell collection. CONCLUSION: Salvage Plerixafor use showed a non-significant improvement in PBSCs collection with a significant increase in cost. Prospective comparative effectiveness studies are warranted to inform the optimal salvage mobilization regimen. To our knowledge, this is the first study from the Middle East to describe the effectiveness and cost effectiveness of Plerixafor.

Hematopoietic stem cell transplantation practice variation among centers in the Eastern Mediterranean Region (EMRO): Eastern Mediterranean Bone Marrow Transplantation (EMBMT) group survey.

INTRODUCTION: This practice survey is conducted to analyze clinical hematopoietic stem cell transplantation (HSCT) practice variability among centers in the WHO Eastern Mediterranean Region (EMRO), as represented by the Eastern Mediterranean Blood and Marrow Transplantation (EMBMT) group. METHOD: This internet based survey was completed by the medical program directors of the EMBMT centers; 17 centers participated. The survey collected data on various clinical aspects of HSCT practice. RESULTS: Consistency in pre HSCT cardiac (100%), pulmonary (82%) and viral screen (100%) was observed. Obtaining informed consent was universal. Pre-HSCT psychological assessment is practiced in 50% of the centers. All centers used single-bedded rooms with HEPA filters. Visitor policy during neutropenic phase and the use of gowns, masks or gloves when examining patients varied among centers. MRSA/VRE screen and use of low bacterial diet were applied in 65% and 82%, respectively. Anti-bacterial prophylaxis is employed in 58% (Auto-SCT) and 60% (Allo-SCT) of the centers. Drug choice varied (cotrimoxazole, ciprofloxacin, levofloxacin, piperacillin-tazobactam); 60% of the centers used penicillin prophylaxis in GVHD patients. PCP prophylaxis is applied in 58% (Auto-SCT) and 87% (Allo-SCT) of the centers; cotrimoxazole is usually used. Anti-viral prophylaxis with acyclovir or, less commonly, valacyclovir is used in 70% (Auto-SCT) and 93% (Allo-SCT) of centers. Anti-fungal prophylaxis is applied in 70% (Auto-SCT), 93% (myeloablative Allo-SCT) and 87% (reduced intensity [RIC] Allo-SCT). Fluconazole is used in all Auto-SCT and majority of Allo-SCT recipients; few centers used other agents (itraconazole, voriconazole, amphotericin B) in Allo-SCT. Prophylactic GCSF use varied among centers: Auto-SCT 77%, myeloablative Allo-SCT 33%, RIC Allo-SCT 27%. Use of ursodeoxycholic acid for venoocclusive disease (VOD) prophylaxis is variable: 60% (Allo-SCT) and 12% (Auto-SCT). Cyclosporine/methotrexate is the most commonly used GVHD prophylaxis in myeloablative Allo-SCT (93%); heterogeneity was seen in RIC SCT. Treatment of steroid refractory acute GVHD varied (ATG 53%, higher steroid dose 40%). CMV monitoring varied between antigenemia (53%) and PCR (40%) techniques. Pre-emptive anti CMV therapy is used in 86% of the centers, while 7% used routine CMV prophylaxis; 7% had no specific CMV management policy. CONCLUSION: Consistency was observed in areas of pre-SCT work up, use of single rooms, HEPA filters and GVHD prophylaxis. Heterogeneity is observed in other practice aspects including other isolation measures, anti-microbial prophylaxis, VOD prophylaxis, growth factor use and treatment of steroid refractory GVHD. Further studies are needed to probe the impact of such practice variations on post-transplant outcome and to ascertain the best clinical practice approach.

Risk adopted allogeneic hematopoietic stem cell transplantation using a reduced intensity regimen for children with thalassemia major.

BACKGROUND: Patients with thalassemia in developing countries have limited access to safe transfusions, regular medical care and chelation therapy. Although allogeneic hematopoietic stem cell transplantation (HSCT) can offer a curative approach, there are limited data on the use of this procedure in developing countries. PROCEDURE: Forty-four patients underwent a risk adopted HSCT from matched related family donor in Jordan. Thirty-one patients (7 Class 1 and 24 Class 2) underwent myeloablative conditioning (MAC) with busulfan (16 mg/kg), cyclophosphamide (200 mg/kg) and antithymocyte globulin (ATG). Thirteen patients all with Class 3, seven with hepatitis C received reduced intensity conditioning (RIC) with busulfan (8 mg/kg), fludarabine (175 mg/m(2)), total lymphoid irradiation (500 cGy) and ATG. RESULTS: All patients had initial neutrophil and platelet engraftment. Secondary graft failure was observed in 2 (6%) patients receiving myeloablative HSCT and 3 (23%) patients receiving RIC. At a median follow up of 64 months (13-108), 43 of 44 patients are alive. The 5-year probability of overall survival (OS) was 97.8% for all patients, 96.8% for patients received MAC and 100% for patients received RIC. The 5-year probability of thalassemia-free survival was 86.4% for all patients, 90.3% and 77% for patients who received MAC and RIC, respectively. CONCLUSION: Implementing a risk-adopted therapy in patient with thalassemia in Jordan can result in an excellent thalassemia free and OS, especially in those at highest risk.

Probability of finding an HLA-matched donor in immediate and extended families: the Jordanian experience.

Information regarding the probability of finding HLA-matched related donor for a patient awaiting hematopoietic stem cell transplantation (HSCT) in developing countries is scanty. We performed a retrospective review of HLA genotypes and related data for 1254 consecutive patients and their families at King Hussein Cancer Center in Amman, Jordan, between 2003 and 2011 to evaluate the chance of finding HLA-matched donor. The median family size was 5 for all patients in the study (range, 1-14), and the average number of donors was 1.4 ± 0.9 for pediatric patients and 1.6 ± 0.9 for adults. Overall, the probability of finding an HLA-matched related donor at our center was 65.5% (60.6% in pediatric patients and 74% in adults). Of the total identified donors, 18% were nonsibling donors after an immediate and/or extended family search in the pediatric group, and 6% were nonsibling donors in the adult group. Overall, 13% of donors were nonsibling donors. We conclude that the probability of finding a matched related donor for HSCT in Jordan is much higher than that reported in Western countries and Asia (65% versus 25%). We expect a similar trend in other developing and Arab countries. We recommend integrating an extended family search before or concomitantly with an unrelated donor search.

High-dose chemotherapy followed by stem cell transplantation in the management of retinoblastoma: a systematic review.

BACKGROUND AND OBJECTIVES: In recent years, there has been an increasing role for stem cell transplantation in the management of retinoblastoma. The aim of this study was to systematically review the role high-dose chemotherapy followed by stem cell transplantation in the treatment of patients with metastatic or relapsed, trilateral or bilateral advanced retinoblastoma, and in patients with tumor at the surgical margin of the optic nerve and/or extrascleral extension. DESIGN: Systematic literature review. METHODS: We performed an extensive PubMed database search on 25 February 2012 for studies describing the use of high-dose chemotherapy followed by stem cell transplantation in the management of patients with retinoblastoma. RESULTS: We located 15 studies that met the inclusion criteria and that included 101 patients. Following treatment for metastatic and relapsed disease, 44 of 77 patients (57.1%) were alive with no evidence of disease at the time of follow-up. However, a higher rate of local relapse developed in patients with CNS metastases (73.1%), which dropped to 47.1% in patients who received thiotepa. In patients with trilateral or bilateral advanced retinoblastoma, 5 of 7 (71.4%) with reported outcome data were alive with no evidence of disease at the time of follow-up. In patients with tumor at the surgical margin of the optic nerve and/or extrascleral extension, 6 of 7 patients (85.7%) were alive with no evidence of disease at the time of follow-up. CONCLUSIONS: Durable tumor control is possible in patients with non-CNS metastases, trilateral or bilateral advanced retinoblastoma, and in patients with tumor at the surgical margin of the optic nerve and/or extrascleral extension. Patients with CNS metastases require thiotepa to improve tumor control.

High-Dose Therapy and Autologous Hematopoietic Progenitor Cells Transplantation for Recurrent or Refractory Hodgkin's Lymphoma: Analysis of King Hussein Cancer Center Results and Prognostic Variables.

Purpose. to evaluate the outcome of patients with Hodgkin's lymphoma who underwent autologous transplantation at KHCC bone marrow transplant program. Patients and Methods. Over 6 years, 63 patients with relapsed or refractory Hodgkin's lymphoma underwent high dose chemotherapy followed by autologous transplant. There were 25.4% patients in complete remission (CR), 71.4% with chemotherapy responsive disease at the time of transplant. Prior to conditioning regimen, 56% received two chemotherapy lines, and, 44% received more than two lines. Results. The main outcomes of the study are the rate of complete remission at day 100, overall survival (OS), relapse-free survival (RFS), The impact of the following variables on OS and RFS: (a) disease status at the time of transplant, (b) number of chemotherapy lines prior to conditioning, (c) age group, (d) time of relapse < or >12 months were investigated. The CR at day 100 was 57%. The median overall survival for the whole group was 40.6 months; the median RFS was 20 months. The only factor which significantly impacts the study outcomes was the number of chemotherapy lines prior to conditioning on OS in favor of patients received two lines. Conclusion. In our study only the number of chemotherapy lines received before conditioning had statistically significant impact on OS.

Hematopoietic stem cell transplantation in the Eastern Mediterranean Region (EMRO) 2008-2009: report on behalf of the Eastern Mediterranean Bone Marrow Transplantation (EMBMT) Group.

BACKGROUND: The Eastern Mediterranean Bone Marrow Transplantation (EMBMT) Group has accumulated over 25 years of data and experience in hematopoietic stem cell transplantation (HSCT), most particularly in hemoglobinopathies, severe aplastic anemia (SAA), and inherited metabolic and immune disorders, in addition to hematologic malignancies peculiar to the region and where recent updates in trends in activities are warranted. OBJECTIVES: To study trends in HSCT activities in the World Health Organization-Eastern Mediterranean (EM) region surveyed by EMBMT between 2008 and 2009. STUDY DESIGN: Retrospective analysis of the survey data, mainly of the cumulative number of transplants, types of transplants (autologous vs. allogeneic), types of conditioning as myeloablative (MAC) vs. reduced intensity conditioning (RIC) and trends in leukemias, hemoglobinopathies, SAA, inherited bone marrow failure syndromes amongst others. RESULTS AND DISCUSSION: Fourteen teams from ten Eastern Mediterranean Region Organization (EMRO) countries reported their data (100% return rate) to the EMBMT for the years 2008-2009 with a total of 2608 first HSCT (1286 in 2008; 1322 in 2009). Allogeneic HSCT represented the majority (63%) in both years. The main indications for allogeneic HSCT were acute leukemias (732; 44%), bone marrow failure syndromes (331, 20%), hemoglobinopathies (255; 15%) and immune deficiencies (90; 5%). There was a progressive increase in the proportions of chronic myeloid leukemia (CML) cases transplanted beyond the first chronic phase (3; 7% of all CML cases in 2008 vs 13; 29% in 2009). The main indications for autologous transplants were plasma cell disorders (345; 36%) Hodgkin disease (256; 27%), non-Hodgkin lymphoma (207; 22%) and solid tumors (83; 9%). RIC continued to show a progressive increase over the years (7% in 2007, 11% in 2008 and 13% in 2009), yet remained relatively low compared to contemporary practices in Europe published by EBMT. The vast majority (95%) of allo-HSCT sources were from sibling donors with a continued dominance of peripheral blood (PB) (1076; 63%), while cord blood transplant (CBT) increased to 83 (5% of allo-HSCT), matched unrelated donor (MUD) remained underutilized (1; 0%) and there were no haploidentical transplants reported. Large centers with >50 HSCT/year showed a plateau of the total number of allo-HSCT over the last 5 years that may be related to capacity issues and needs further study. CONCLUSIONS AND RECOMMENDATIONS: There is an overall increased rate of HSCT in the EMRO region with a significant increase in utilization of CBT and allogeneic PB-HSCT as a valuable source. However, further research on outcome data and development of regional donor banks (CB and MUD) may help facilitate future planning to satisfy the regional needs and increase collaboration within the group and globally.

Trends of hematopoietic stem cell transplantation in the Eastern Mediterranean region, 1984-2007.

Hematopoietic stem cell transplantation (HSCT) activity was surveyed in the 9 countries in the World Health Organization Eastern Mediterranean region that reported transplantation activity. Between the years of 1984 and 2007, 7933 transplantations were performed. The number of HSCTs per year has continued to increase, with a plateau in allogeneic HSCT (allo-HSCT) between 2005 and 2007. Overall, a greater proportion of transplantations were allo-HSCT (n = 5761, 77%) compared with autologous HSCT (ASCT) (n = 2172, 23%). Of 5761 allo-HSCT, acute leukemia constituted the main indication (n = 2124, 37%). There was a significant proportion of allo-HSCT for bone marrow failures (n = 1001, 17%) and hemoglobinopathies (n = 885, 15%). The rate of unrelated donor transplantations remained low, with only 2 matched unrelated donor allo-HSCTs reported. One hundred umbilical cord blood transplantations were reported (0.017% of allo-HSCT). Peripheral blood stem cells were the main source of graft in allo-HSCT, and peripheral blood stem cells increasingly constitute the main source of hematopoietic stem cells overall. Reduced-intensity conditioning was utilized in 5.7% of allografts over the surveyed period. ASCT numbers continue to increase. There has been a shift in the indication for ASCT from acute leukemia to lymphoproliferative disorders (45%), followed by myeloma (26%). The survey reflects transplantation activity according to the unique health settings of this region. Notable differences in transplantation practices as reported to the European Group for Blood and Marrow Transplantation over recent years are highlighted.

Successful stem-cell mobilization and transplantation using plerixafor in a patient with a germ cell tumor.

High-dose chemotherapy followed by autologous hematopoietic stem-cell transplantation is an important treatment option for a variety of malignancies. Peripheral blood stem cells (PBSCs) have replaced bone marrow-derived cells as source of stem cells in transplants, and the success of a transplant depends highly on the number of PBSCs mobilized, collected and eventually infused. Nevertheless, a good percentage of patients fail to mobilize stem cells when growth factors alone or in combination with chemotherapy are used. Recently, plerixafor has been approved as a novel agent to mobilize stem cells in multiple myeloma and lymphoma patients. Data on the efficacy and safety of plerixafor in solid tumors is lacking. We report the successful stem cell mobilization and transplantation for a patient with a germ cell tumor using plerixafor.

Haploidentical stem cell transplantation as a salvage therapy for cord blood engraftment failure in a patient with Fanconi anemia.

A 7-year-old male with Fanconi Anemia who developed primary graft failure following one antigen-mismatched unrelated cord blood transplantation and a nonradiation-based conditioning, underwent a second hematopoietic stem cell transplantation (HSCT) from his 2-loci mismatched haploidentical father, using a nonradiation-based regimen, 79 days after the first HSCT. A sustained hematological engraftment was achieved at 9 days post-second HSCT. At 15 months post-second HSCT; the patient demonstrated normal blood counts, sustained donor chimerism, and no evidence of GVHD. Haploidentical HSCTs as primary or secondary sources of stem cells, with appropriate T-cell depletion, may be a readily available option in the absence of HLA-matched related or unrelated donors.