Fludarabine and Oral Busulfan: A Low Toxicity Conditioning Regimen When Plasma Level Targeting and Intravenous Busulfan Is Not Available. A Brazilian Experience.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5302-5302
Author(s):  
Belinda P. Simoes ◽  
M. Souza ◽  
Marcos Mauad ◽  
Eduardo J.A. Paton ◽  
Fabiano Pieroni ◽  
...  
Keyword(s):  
Plasma Level ◽  
Complete Remission ◽  
Cause Of Death ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Chronic Phase ◽  
Sinusoidal Obstruction Syndrome ◽  
Age Range ◽  
Active Disease

Abstract Fludarabine in combination with intravenous Busulfan has been used to reduce treatment related mortality (TRM) in allogeneic stem cell transplantation (SCT). Considering that busulfan has erratic bioavailability and unpredictable intestinal absorption, previous investigations have used intravenous busulfan with plasma-targeted levels dosing. In Brazil neither intravenous Busulfan nor routine plasma level measurement of Busulfan are available. In this report we retrospectively analyze 74 patients (median age 32 y.o.) submitted to SCT using a Fludarabine and oral Busulfan based conditioning regimen. Forty three patients had acute myeloid leukaemia (AML, age range 5 to 58) and 31 patients chronic myeloid leukemia (CML, age range 19 to 58). Among the AML patients, 44% were in first remission (CR1), 23% in second remission (CR2) and 33% patients had active disease (AD) at the time of transplant. Among CML patients, 65% were in chronic phase (CML-CP), 29% in accelerated phase (CML-AP) and 6% in blast crisis (CML-BC). Fludarabine 30 mg/m2 and oral Busulfan 4 mg/kg was given for 4 days with Cyclosporine A and Methotrexate GVHD prophylaxis. For patients with unrelated donors, ATG were added. All patients engrafted (median 14 days). At a median follow up time of 180 days non-relapse mortality was 5%. Seventeen patients (23%) died (12 AML and 5 CML patients). Among survivors (57 patients), 56 remain in complete remission. One patient with a refractory AML and a complex karyotype relapsed on day +90. One patient died of severe sinusoidal obstruction syndrome (SOS). Acute GVHD occurred in 14 (19%) patients (10 AML and 4 CML) none of them grade III or IV. Chronic GVHD occurred in 11 patients so far, being the cause of death in 2 patients. Major cause of death was relapse of disease in patients transplanted with active disease. Only three AML patients in CR1 died (chronic GVHD, sepsis and fulminant hepatic failure) in contrast to 60% of patients with active disease (88% relapsed). One patient with CML-CP died with a relapse in CML-BC, the remaining 19 (92%) patients are alive in complete remission. One patient transplanted in CML-AP died (cGVHD and zygomykosis) and all patients transplanted in BC died of their disease. Actuarial 1-year overall survival for CML is 92% and 54% (CP and AP/BC respectively, p=0,04) and for AML 72% and 23% (CR1/CR2 and AD, respectively, p=0,005). These preliminary data show that oral Busulfan and Fludarabine can safely be used without plasma level monitoring. The follow up time is short and the effect on the control of CML cannot be concluded. However AML has been effectively controlled as far as patients were transplanted in remission (AML-CR1 and CR2). For patients in more advanced disease stages this regimen is not optimal. However, this regimen is safe and may improve the results in early stages of AML and CML even in countries with limited resources in health care.

Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) in Patients with Haematological Lymphoid Malignancies: Long Term Follow-up in a Single Centre Series.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4326-4326
Author(s):  
Malek Benakli ◽  
Redhouane Ahmed nacer ◽  
Amina Talbi ◽  
Rachida Belhadj ◽  
Farih Mehdid ◽  
...  
Keyword(s):  
Complete Remission ◽  
Hodgkin Lymphoma ◽  
Median Time ◽  
Conflicts Of Interest ◽  
Late Onset ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Lymphoid Leukaemia ◽  
Autologous Transplant

Abstract Abstract 4326 Background Patients (pts) with recurrent and refractory haematological lymphoid malignancy (HLM) have a very limited survival expectance. RIC allo-SCT has been proposed as a strategy for retaining the graft versus malignancy effect of allo-SCT while decreasing transplant related mortality (TRM). Here, we retrospectively studied a series of 32 pts treated by RIC allo-SCT. Patients and methods Between April 2001 and November 2007, 32 pts with HLM underwent RIC allo-SCT with an HLA-identical sibling donor. Fifteen pts with multiple myeloma, 7 pts with Non-Hodgkin lymphoma, 6 pts with Chronic lymphoid leukaemia, 3 pts with Hodgkin lymphoma and 1 pt with Waldenstrom disease. At time of allo-SCT, 10 pts were in complete remission (3 received prior autologous transplant) and 22 in refractory/progressive disease (6 received prior autologous transplant). Median age was 38 years (range, 28-60) and the sex-ratio (M/F) 2,2. Median time from diagnosis to RIC allo-SCT was 18 (range,6-76) months. The conditioning regimen included Fludarabine 150mg/m2 and Melphalan 140mg/m2. GVHD prophylaxis consisted of association cyclosporine (cSA) and mycophenolate (MMF). All pts received G-CSF mobilised peripheral blood stem cells, with a median CD34+ cell count: 6,2.106/kg (range, 1.9-13,6). Results Neutropenia occurred in all pts (100%) and the median duration of aplasia was 9 (range, 5-16) days. Only 10 pts (31 %) required red blood cells transfusions and 23 pts (71 %) needed platelets transfusions. Acute GVHD was observed in 15 cases (47 %) including 10 cases of grade II-IV. Fifteen pts (75 %) had chronic GVHD, of whom 9 with an extensive form. Four pts (12 %) had CMV reactivation at a median time 60 (range, 52-80) days after transplantation. Six pts (18 %) had late onset relapse at a median time of 13 (range, 4-45) months. TRM was 43 % at one year after RIC allo-SCT. With a median follow-up of 60 (range 18-97) months, 12 pts (37,5 %) are still alive in complete remission with full donor chimerism. Twenty pts (62,5 %) have died (5 early severe infections, 10 GVHD, 3 after relapse, one myocardial infarction, and one accident). Overall and progression-free survivals at 8 years are 31 % and 30 % respectively. Conclusion This study, after a large follow-up, suggests that RIC allo-SCT is a potential therapy for refractory or progressive HLM. However, TRM is still high likely due to the inclusion of refractory and heavily pretreated pts with many comorbid conditions. Disclosures: No relevant conflicts of interest to declare.

Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) in Patients with Multiple Myeloma (MM): Long Term Follow-up in a Single Centre Series

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4398-4398
Author(s):  
Malek Benakli ◽  
Redhouane Ahmednacer ◽  
Amina Talbi ◽  
Farih Mehdid ◽  
Rachida Belhadj ◽  
...  
Keyword(s):  
Complete Remission ◽  
Median Time ◽  
Acute Gvhd ◽  
Late Onset ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Peripheral Blood Stem Cells ◽  
Heavily Pretreated ◽  
Blood Stem Cells

Abstract Background: RIC allo-SCT has been proposed as a strategy for retaining the graft versus myeloma effect of allo-SCT while decreasing transplant related mortality (TRM). Here, we retrospectively studied a series of 15 patients (pts) with MM treated by RIC allo-SCT. Patients and methods: Between April 2001 and December 2007, 15 pts with MM underwent RIC allo-SCT with an HLA-identical sibling donor. Initially, 8 pts had MM with Ig G, one IgA, 2 light chains, 3 non-secretory and one undetermined. Three pts were stage II and 12 stages III. At time of allo-SCT, 6 pts were in complete remission and 9 in refractory/progressive disease (2 received prior autologous transplants). Median age was 48 years (range, 38–60) and the sex-ratio (M/F) 1,5. Median time from diagnosis to RIC allo-SCT was 18 (range, 6–76) months. The conditioning regimen included Fludarabine 150mg/m2 and Melphalan 140mg/m2. GVHD prophylaxis consisted of association cyclosporine (cSA) and mycophenolate (MMF). All pts received G-CSF mobilised peripheral blood stem cells, with a median CD34+ cell count: 4,5.106/kg (range, 1.92–13). Results: Neutropenia occurred in all pts and the median duration of aplasia was 8 (range, 5–14) days. Only 3 pts (20 %) required red blood cells transfusions and 12 pts (80 %) needed platelets transfusions. Acute GVHD was observed in 6 cases (40 %) including 4 cases of grade II–IV. Eight pts (72 %) had chronic GVHD, of whom 5 with an extensive form. Three pts (20 %) had CMV reactivation at a median time 91 (range, 53–158) days after transplantation. Four pts (26 %) had late onset relapse at a median time of 826 (range, 248–1370) days. TRM was 33 % at one year after RIC allo-SCT. With a median follow-up of 50 (range 14–86) months, 5 pts (33 %) are still alive in complete remission with full donor chimerism. Ten pts (66 %) died (2 early severe infections, 3 acute GVHD, 3 after relapse, one myocardial infarction, and one public highway accident). Overall and progression-free survivals at 7 years are 37,5 % and 31,2 % respectively. Conclusion: This study suggests that RIC allo-SCT is a potential therapy for relapsed MM. However, TRM and relapse remain a matter of concern, likely due to the inclusion of refractory and heavily pretreated pts with many comorbid conditions. Future protocols, should aim for better patient selection, focussing on those pts in first chemosensitive relapse.

Comparison of Two Different Rabbit-ATG Preparations on the Outcome after Unrelated Stem Cell Transplants for Chronic Phase CML.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2768-2768
Author(s):  
Michael Schleuning ◽  
Joerg Kaltenhaeuser ◽  
Mazur Heshmat ◽  
Irena Burlakova ◽  
Dirk Judith ◽  
...  
Keyword(s):  
Overall Survival ◽  
Treatment Option ◽  
Cox Regression ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Chronic Phase ◽  
Matched Pair ◽  
Time Interval ◽  
Allogeneic Bone

Abstract Allogeneic bone marrow transplantation (BMT) remains a curative treatment option for patients with CML. Unrelated donor (URD)-BMT is a realistic treatment option for a large group of patients (pts) in need. To ensure engraftment and to reduce the incidence of acute and chronic GVHD antithymocyte globulin (ATG) has been incorporated into the preparative regimen by many centers. However, little is known if the various preparations available yield comparable results. This analysis reports a single center experience on URD-BMT in chronic phase CML pts with special emphasis on the different ATG preparations used (immunization of rabbits with human thymus, ATG Merieux/Sangstat/Genzyme (ATG-M) or with the leukemic cell line Jurkat, ATG Fresenius (ATG-F)). Since 1995 61 pts (40 male; 21 female) with CML received an URD-BMT. Three pts (1 male, 2 female) from the ATG-F group were excluded because they also received ATG-M after early graft failures, which possibly were attributable to dose adjustments for obesity, to HHV6 infection, and prior use of Imatinib mesylate. Median patient age was 38 years (16–61). 46 pts were transplanted in first chronic phase and 12 in accelerated or second chronic phase and 76% received a fully matched (HLA-A, B, DRB1) transplant. 13 pts received a 1 antigen and 1 patient a 2 antigen mismatched transplant. All pts received in vivo T-cell depletion with ATG during conditioning. 46 pts received ATG-M and 12 pts ATG-F. As analyzed by July 2004 after a median follow-up of 3.3 years for surviving pts. the estimated probability for overall survival is 61%. For eventfree survival, despite the low number and short follow-up of pts who received ATG- F, there was a strong trend (p=0.0611; Log-Rank) in favor of ATG-F as compared to ATG-M, which reached significance in a matched pair analysis (p=0.03). In multivariate cox regression analysis for pretransplant risk assessment for overall survival a time interval of more than a year from diagnosis to transplant (RR 2.5, 1.0–6.3) and a CMV-IgG negative donor for a CMV-IgG positive patient (RR 2.9, 1.1–7.7) and for eventfree survival again the time interval from diagnosis to transplant (RR 2.3, 0.9–5.7) and the use of ATG-M (RR 4.7, 0.6–35.2) were independent negative predictors. The incidence of acute GVHD grade III - IV was higher in the ATG-M group (17% vs. 8%) as was the rate of extensive chronic GVHD (29% vs. 0%). This also translated into a higher risk of death without relapse (35% vs. 8%). However, these observations may be biased to some extent, since most patients who were receiving ATG-F received a conditioning regimen based on intravenous busulfan, whereas most patients who were receiving ATG-M received conditioning regimens mainly based on oral untargeted busulfan, although the type of conditioning was no independent risk factor in the Cox regression model used. Nevertheless, our data indicate that the results of URD-BMT in chronic phase CML patients can further be improved by reducing the rate of acute and chronic GVHD. A promising approach seems to be a conditioning regimen based on intravenous busulfan incorporating ATG-Fresenius.

Intravenous Compared to Oral Busulfan with Cyclophophamide for Allogeneic Hematopoietic Progenitor Cell Transplant Conditioning for AML and MDS.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3475-3475
Author(s):  
Ronald Sobecks ◽  
Lisa Rybicki ◽  
Matt Kalaycio ◽  
Robert Dean ◽  
Steven Andresen ◽  
...  
Keyword(s):  
Progenitor Cell ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Hematopoietic Progenitor Cell ◽  
Sinusoidal Obstruction Syndrome ◽  
Cell Transplant ◽  
Hematopoietic Progenitor ◽  
Cell Dose ◽  
Unrelated Donors

Abstract Abstract 3475 Busulfan (Bu) is commonly used with cyclophosphamide (Cy) as a conditioning regimen for allogeneic hematopoietic progenitor cell transplantation (HPCT). Recently, intravenous (IV) Bu has often replaced oral Bu for conditioning. We have previously reported that substituting IV for oral Bu was associated with a lower rate of relapse, and superior relapse-free and overall survivals for relapsed or refractory non-Hodgkin lymphoma patients undergoing autologous HPCT (Dean et al. Br J Haematol 2010 Jan;148(2):226-34). We retrospectively compared the outcomes of 135 consecutively treated AML and MDS patients who underwent allogeneic HPCT at our institution from 5/2001 through 10/2009 with BuCy using oral (n = 93) or IV (n = 42) Bu, without dose adjustment. The analysis included matched related (n=97) and 8/8 HLA matched unrelated donors (n=38). Oral Bu was administered as 1 mg/kg every 6 hours for 16 doses while IV Bu was administered as 0.8 mg/kg every 6 hours for 16 doses (days –8 through -4) followed by Cy 60 mg/kg/day × 2 (days –3 and –2). The IV Bu patients were older (median age 49 vs. 47 yrs, respectively, p=0.037), more commonly had unrelated donors and peripheral blood stem cells for their HPCT cell source than those treated with oral Bu. There were no significant differences between the groups with regards to patient gender, race, CIBMTR comorbidity index score, number of prior chemotherapy regimens, pre-transplant disease status (each group had 45% of patients in CR1 or CR2), donor-recipient gender relationships or nucleated cell dose infused. The IV Bu group had a higher median CD34+ cell dose infused than those who received oral Bu (3.34 vs. 2.19 ×106/kg, respectively, p=0.028). The IV Bu patients experienced a significantly lower incidence of mucositis (3% vs. 55%, p<0.001) and less severe mucositis (median OMAS scores 0 vs.0.08, respectively, p<0.001). However, there were no significant differences between the IV and oral Bu groups in days until neutrophil and platelet count engraftment, length of transplant hospitalization, incidence of acute or chronic GVHD, sinusoidal obstruction syndrome, and 100 day mortality. At this time 26 (62%) of the IV Bu patients and 33 (36%) of the oral Bu patients are alive, however, the median follow-up was substantially longer for the oral Bu group (50 vs. 13 months, p<0.001). Disease relapse was the most common cause of death for both the IV and oral Bu patients accounting for approximately 50% of deaths in each group. The 1 and 2 year transplant-related mortality for the IV Bu patients was 21% for both, while that for the oral Bu group was 23% and 29%, respectively. The 1 and 2 year relapse mortality for the IV Bu patients was 21% for both, while that for the oral Bu group was 24% and 29%, respectively. Substituting IV for oral Bu reduces variability in drug exposure and potentially improves safety as suggested from our finding of significantly less severe oral mucositis in the IV Bu group. Further follow-up of the IV Bu group is required to adequately assess for a survival benefit. Whether pharmacokinetic-based Bu dosing can improve outcomes after allogeneic HPCT in this setting is worthy of further study. Disclosures: Sobecks: Otsuka Pharm.: Research Funding.

scholarly journals Feasibility and Outcomes of Haploidentical Transplantation for Elderly Patients with Advanced Hematological Malignancies: The MD Anderson Cancer Center Experience

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1245-1245 ◽  
Author(s):  
Sameh Gaballa ◽  
Piyanuch Kongtim ◽  
Gabriela Rondon ◽  
Julianne Chen ◽  
Uday Popat ◽  
...  
Keyword(s):  
Stem Cell ◽  
Complete Remission ◽  
Hematological Malignancies ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Cancer Center ◽  
Platelet Recovery ◽  
Matched Donor ◽  
Active Disease

Abstract Background Haploidentical stem cell transplantation (HaploSCT) is an acceptable option for younger patients (pts) with advanced hematological malignancies without a human leukocyte antigen (HLA)-matched donor; however, it remains unclear whether older pts would benefit from such a transplant. Here, we report the outcomes of pts age 55 years or older who received a T-cell–replete HaploSCT with a reduced-intensity conditioning regimen using fludarabine-melphalan and post-transplant cyclophosphamide (PTCy) as previously described by us. Methods We retrospectively analyzed data from 30 pts (20 [67%] with acute myeloid leukemia [15 with high-risk disease], 4 [13%] with myelodysplastic syndromes, 3 [10%] with lymphoma, and 3 with other diagnoses) who received their first HaploSCT between 2009 and 2014. Twenty-one pts (70%) received conditioning with fludarabine 40 mg/m2 (Days -6, -5, -4, -3) and melphalan 100 mg/m2 (Day -8) with thiotepa 5 mg/kg (Day -7) or 2 Gy total-body irradiation (FM100). Nine pts (30%) received a higher melphalan dose of 140 mg/m2. GVHD prophylaxis consisted of PTCy 50 mg/kg on day +3 and +4 after HaploSCT and tacrolimus and mycophenolate for 6 and 3 months, respectively. Sixteen pts (53%) were in remission at the time of transplant. Donors were children (83%) and siblings (17%). All patients but 1 received bone marrow as a stem cell source. Results Thirty pts (57% men) with a median age of 61 years (range, 55-69 years) received a HaploSCT between 2009 and 2014. One pt had early death on day +7 from a viral infection. All other pts engrafted successfully (100% engraftment), with 84% achieving 100% donor chimerism at day 30. The median times to ANC and platelet recovery were 19 days (range, 13-27 days) and 28 days (range, 19-46 days), respectively. CMV reactivation occurred in 21 pts (70%) and was treated preemptively. The rates of grade II-IV and III-IV acute GVHD at day 100 were 30% and 10%, respectively; chronic GVHD occurred only in 3 pts (10%) (2 limited, 1 extensive). After a median follow-up duration of 18 months, 18 pts (60%) were alive and disease-free. The 1- and 2-year overall survival rates were 60% and 55%, respectively (62% for pts in complete remission and 41% for pts with active disease at 2 years, log-rank= 0.23), and the 1- and 2-year progression-free survival rate was 55% (63% at 1 and 2 years for pts in complete remission and 40% for pts with active disease at 1 year) (Figure). The 100-day and 2-year cumulative incidences of non-relapse mortality were 17% and 21%, respectively (12% and 18%, respectively, for pts in remission at transplant). Causes of death included relapsed disease (n=6), infection (n=3), chronic GVHD (n=1), and regimen toxicity (n=1). Conclusions HaploSCT for older pts up to age of 70 years is associated with low rates of acute and chronic GVHD, acceptable NRM, and excellent survival. Age alone does not appear be a barrier against successful transplantation from a haploidentical donor and should be offered to all pts in need of a transplant without an HLA-matched donor. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Molecular Remission Can Be Attained in Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) and Follicular Lymphomas after Reduced Intensity Conditioning (RIC) and Allogeneic Stem Cell Transplantation (ALLO-SCT).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2317-2317
Author(s):  
Lucia Farina ◽  
Matteo Carrabba ◽  
Anna Dodero ◽  
Elena Rizzo ◽  
Elisabetta Zorzan ◽  
...  
Keyword(s):  
Nested Pcr ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Lymphocytic Leukemia ◽  
Clinical Relapse ◽  
Molecular Remission ◽  
Continuous Increase ◽  
Taqman Pcr ◽  
Follicular Lymphomas

Abstract RIC followed by allo-SCT is an effective salvage treatment for some relapsed hematologic malignancies due to the postulated graft versus tumour (GVT) effect. In order to evaluate the quality of the clinical response, we have investigated the molecular status of patients receiving allo-SCT for relapsed disease. Forty-four patients (19 chronic lymphocytic leukemias (CLL), 21 follicular lymphomas (FCL) and 4 small lymphocytic lymphomas (SLL)) were enrolled in a prospective phase II study. The median age was 54 years (range: 32–69 years). The median number of previous chemotherapy regimens was 2 (range: 1–5) and 23% of patients had already failed an auto-SCT. Before transplant 34% of patients were chemorefractory and 34% of the chemosensitive patients were in complete remission (CR). The conditioning regimen consisted of thiotepa 10mg/kg, fludarabine 60mg/ms and cyclophosphamide 60mg/kg; short course of methotrexate and cyclosporin were used as GVHD prophylaxis. Minimal residual disease (MRD) was monitored by nested PCR for IgH or Bcl-2 genes; in PCR-positive patients a TaqMan based quantitative monitoring was also employed. All patients engrafted. On day +30 after transplant 39% of patients achieved CR. Acute GVHD (aGVHD) was observed in 57% of patients and 52% of 42 evaluable patients developed chronic GVHD; no difference in the incidence of GVHD between FCL and CLL/SLL was observed. In 30 of 44 patients (68%) a PCR marker for MRD monitoring was found. Twenty-five patients (10 CLL, 2 SLL, 13 FCL) of 37 patients in CR after allo-SCT were monitored by nested PCR and 4 PCR-positive patients were monitored by TaqMan PCR. At a median molecular follow up of 15 months (range: 3–62) 15 of 25 patients (60%) were alive and in molecular remission; one CLL patient died of TRM in molecular remission (MR); five of these patients were chemorefractory. Nine patients (3 FCL, 5 CLL, 1 SLL) never achieved PCR negativity and 3 of them relapsed (2 CLL; 1 SLL) after a median time of 270 days. In one of these patients the TaqMan PCR system could detect a continuous increase of tumour genomes in the marrow prior to the clinical relapse. The SLL patient achieved MR after chemotherapy and DLI, developing limited cGVHD; the other two patients never developed GVHD, even after DLI. Eighty percent of PCR-negative patients developed GVHD and it preceded or was concomitant with the achievement of MR. The better molecular outcome of FCL seems to be due to a longer follow up (19 months vs 12 months) if compared to CLL/SLL, in which a slow clearance of MRD has been observed. In conclusion, MR can be achieved in relapsed and chemorefractory patients affected by indolent lymphoproliferative disorders; quantitative PCR monitoring can be used to modulate post-transplant immunotherapy; a longer follow up is warranted to evaluate if the GVT effect can sustain MR in the long-term.

Outcome of Allogeneic Hematopoietic Cell Transplantation (HCT) for Patients with Severe Aplastic Anemia (SAA) above the Age of 40 Years.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3019-3019
Author(s):  
Dario Sangiolo ◽  
Rainer Storb ◽  
Wendy Leisenring ◽  
George Georges
Keyword(s):  
Median Time ◽  
Immune Suppression ◽  
Chronic Gvhd ◽  
Immunosuppressive Treatment ◽  
Conditioning Regimen ◽  
Term Survival ◽  
Allogeneic Hct ◽  
Number Of Patients ◽  
Clinical Records

Abstract Allogeneic HCT for SAA is definitive curative therapy for this otherwise fatal hematologic disease. For younger SAA patients, long-term survival of approximately 90% can be expected after HCT from HLA-identical siblings with cyclophosphamide/ antithymocyte globulin (CY/ATG) conditioning and post-grafting methotrexate/cyclosporine (MTX/CSP) immunosuppression. Most transplant center guidelines and many published reports restrict allogeneic HCT to SAA patients under the age of 40 years, due to concern of increased morbidity and mortality from HCT in older patients. We reviewed the clinical records of all 20 patients with a diagnosis of SAA who were treated with HCT from an HLA-identical sibling at the Fred Hutchinson Cancer Research Center from July 1988 to January 2006 and were above the age of 40 years at the time of HCT. The conditioning regimen consisted of CY/ATG for all but 2 patients who did not receive ATG. MTX and CSP were used as post grafting immunosuppression. The median age of the 10 men and 10 women was 47 (40–63) years. The median time from diagnosis to HCT was 2.7 (0.8–48.5) months. Ten patients had previously received immunosuppressive treatment and all 20 patients had received multiple red blood cell and platelet transfusions before HCT. The median follow-up of surviving patients was 86 (range, 17–194) months after HCT. One patient had graft rejection on day 28 and is alive and well following reconditioning and repeat marrow grafting from original donor. The incidence of acute grades II and III graft-versus-host-disease (GVHD) was 41% and 6%, respectively, the incidence of chronic GVHD (cGVHD) was 37% (6 patients). Overall survival was 70% (fig. 1). Three patients died before engraftment: from preexisting disseminated aspergillosis (n=1), congestive heart failure likely related to CY toxicity (n=1) and preexisting disseminated candidiasis (n=1) on days 2, 3 and 6, respectively. Three patients died from infections on days 83, 179 and 223; in the latter 2 cases, the infections were related to cGVHD and its treatment. The median time to discontinuation of immune suppression was 6 (range, 6–46) months (fig. 1). At last follow-up, 2 patients remain on immune suppression for treatment of cGVHD at 24 and 41 months, respectively. Three patients experienced avascular joint necroses 3, 6 and 9 years after HCT; they had cGVHD (n=2) and/or received extensive steroid treatment before HCT (n=2). Two patients developed superficial basal cell carcinoma at 5.5 and 15 years after HCT. Our data suggest that allogeneic HCT from sibling donor can be successfully extended to SAA patients older than 40 years. Although the number of patients are limited, survival after HLA-identical sibling HCT appears superior to published results of immune suppression therapy for patients >40 years of age. Pre-HCT cardiac screening is indicated to minimize the risk of conditioning related toxicity. Improved treatment to effectively treat or prevent cGVHD and associated infections remain important issues. Figure Figure

Unrelated Donor Hematopoietic Cell Transplantation after Non-Myeloablative Conditioning for Patients with High Risk Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3158-3158
Author(s):  
Roberto Sorasio ◽  
Luisa Giaccone ◽  
Francesca Patriarca ◽  
Vittorio Montefusco ◽  
Stefano Guidi ◽  
...  
Keyword(s):  
Disease Progression ◽  
Initial Treatment ◽  
Response Rate ◽  
Treatment Plan ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
High Response ◽  
High Dose ◽  
Unrelated Donor

Abstract Allografting can induce long-term molecular remissions and possibly cure in myeloma patients. The recent development of non-myeloablative conditionings has reduced the transplant-related mortality (TRM) typically associated with myeloablation and extended the eligible age for transplantation. Moreover, high response rates are reported especially when allografting is preceded by cytoreductive high dose chemotherapy. We investigated the feasibility of unrelated donor non-myeloablative transplantation as either part of the initial treatment plan or as salvage treatment in heavily pre-treated patients. Twenty-two patients underwent non-myeloablative allografting, 10 as part of their initial treatment and 12 at disease relapse. Donors were matched for HLA-A, B, C, DRB1 and DQB1 by high-resolution typing. Only one single class I allele disparity was allowed. Conditioning regimen consisted of fludarabine 90 mg/m2 and 2 Gy total body irradiation. GVHD prophylaxis included oral cyclosporine (CyA) and mycophenolate mofetil (MMF). CyA was administered at 6.25 mg/Kg every 12 hours from day -3; levels were targeted to the upper therapeutic range (450–500 ng/ml, Abbott TDX, Abbott Park, IL) for the first month post-transplant. In the absence of GVHD, CyA was tapered from day +100 and discontinued on day +177. MMF was administered from day 0 after PBSC infusion to day +40 at 15 mg/Kg every 8 hours, and then tapered till day +96. Twenty/22 (91%) patients readily engrafted. Two patients experienced graft failure and eventually recovered autologous hematopoiesis. After a median follow up of 11 months (3–27), TRM was 18% and 16/22 patients (73%) are alive. Deaths occurred in 10% of patients transplanted upfront and in 42% of those transplanted at relapse: 3 patients died from infections, 1 from hemolytic uremic/ thrombotic thrombocytopenic purpura syndrome, and 2 from disease progression (both were transplanted at relapse). Ten/20 engrafted patients (50%) had grade II–IV acute GVHD (10% grade III–IV), and 59% had extensive chronic GVHD. Overall response rate was 60% (including 20% CR): 78% in patients transplanted upfront (no disease progression observed) and 45% in those transplanted at relapse. In the two groups, progression-free and one year event-free survival were 100% and 44% (p<0.025), and 90% and 28% respectively (p<0.005). Unrelated donor non-myeloablative allografting is feasible with relatively low TRM and high response rate. Graft-versus-myeloma effect appears to be more efficient when patients are treated soon after diagnosis. Longer follow-up is needed to assess response duration.

No Improvement of Overall-Survival in Children with High-Risk Acute Myeloid Leukemia by Stem Cell Transplantation in 1st Complete Remission.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 320-320 ◽  
Author(s):  
Dirk Reinhardt ◽  
Bernhard Kremens ◽  
Martin Zimmermann ◽  
Josef Vormoor ◽  
Michael Dworzak ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Complete Remission ◽  
Children And Adolescents ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Hla Typing ◽  
Unrelated Donor ◽  
The Impact

Abstract One aim of the AML-BFM 98 study was to evaluate prospectively the impact of matched sibling donor (MSD)-SCT in 1st complete remission (CR) in children with high-risk (HR)-AML. Patients: Between 7/1998 and 3/2004 494 children and adolescents were enrolled in the studies AML-BFM 98 and the AML-BFM 98 Interim 2003. Patients with favorable cytogenetics [t(8;21), inv(16), t(15;17)], corresponding morphology (AML FAB M1/2 with Auer rods, M4eo, M3) and < 5% blasts on day 15 were defined as standard risk (SR)-group (n=177). All others were stratified to HR-group (n=317) and eligible for SCT in 1st CR. Out of 275 patients achieving 1st CR (87%) 63 patients had a MSD and 188 had no MSD (intent-to-treat group, ITT) while 24 patients had to be excluded due to missing HLA typing or initial refusal to SCT. Thirty-six patients received MSD-SCT (=as-treated group), another two children were transplanted from a matched unrelated donor (MUD) although an MSD was available. The reasons not performing SCT in 1st CR in the remaining 25 children with a donor available were early relapse (n=7), death in CR (n=2), clinical reasons (n=8), or refusal of SCT (n=8). Chemotherapy (CHT) only was given in 192 patients (n=167 without MSD, n=25 with a MSD). Another 21 children were transplanted from an unrelated donor (n=18), family donor (n=1), haploidentical donor (n=2). The reasons were slow response, very poor cytogenetics or other clinical reasons. Treatment: All patients received double induction and consolidation. MSD-SCT in 1st was scheduled after 4 blocs of treatment. Children who were not transplanted in 1st CR received intensification and a 1-year maintenance therapy. The recommended conditioning regimen consisted in busulfan and cyclophosphamide. Results ITT analysis revealed no significant differences in of 5 year disease-free survival (DFS) and overall survival (OS) between children with or without a donor (no donor vs. donor: DFS 43±4% vs. 47±7% plog rank 0.52; OS 56±4% vs. 58±9%, plog rank 0.16). The as-treated analysis gave similar results: CHT only vs. MSD-SCT: DFS 35±11% vs. 59±9% p Mantel-byar 0.13; OS 59±13% vs. 62±12%, p Mantel-byar 0.51). The major reasons of treatment failures were relapses in all groups [CHT only n=100 (52%), MSD-SCT n=13 (34%), MUD-SCT n=9 (50%)]. A 2nd CR was achieved in 71% of the CHT only group (n=74). After SCT in 2nd CR, OS was 40±6%. By contrast, only two children (9%) of 22 children after relapse following SCT in 1st CR could be salvaged. Severe late adverse events (e.g. severe chronic GvHD CTC grade IV, destruction of big joints, intracerebral bleedings) were more frequent in children transplanted in 1st CR (15%) than in those with CHT only (including SCT in 2nd CR; 5%, p×2< 0.05). Conclusion: In the population-based, prospective multi-center study AML-BFM 98 allogeneic MSD-SCT in 1st CR showed no advantage in children and adolescents with HR-AML. Considering the higher toxicity of allogeneic SCT, in the ongoing trial AML-BFM 2004, this SCT (MSD or MUD) is restricted to patients in 2nd CR and refractory AML.

Outcomes of 40 Adult Patients after Double Cord Blood Transplantation Using a Reduced Intensity Chemotherapy Conditioning Regimen.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 605-605
Author(s):  
Karen K. Ballen ◽  
Corey Cutler ◽  
Thomas R. Spitzer ◽  
Beow Yeap ◽  
Steve McAfee ◽  
...  
Keyword(s):  
Cord Blood ◽  
Total Dose ◽  
Aplastic Anemia ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Cord Blood Unit ◽  
Reduced Intensity ◽  
Related Mortality

Abstract Umbilical cord blood is an alternative stem cell source for patients without matched related or unrelated donors. However, single cord blood unit transplantation in adults is associated with high transplant related mortality, mostly due to infection. In this study, we used a reduced intensity conditioning regimen followed by infusion of two partially matched cord blood units. The conditioning regimen was fludarabine 30mg/m2/day Days -8,-7,-6,-5,-4,-3 (total dose 180mg/m2), melphalan 100mg/m2/day Day -2, and rabbit antithymocyte globulin (thymoglobulin) 1.5 mg/kg/day Days -7,-5,-3,-1 (total dose 6.0 mg/kg). Cord blood units were a 4/6 or better HLA A, B, DR match with each other and with the patient, and contained a minimum combined pre-freeze cell dose of 3.7 x 107NC/kg. GVHD prophylaxis was cyclosporine and mycophenolate mofetil, for the first 21 patients, and tacrolimus and sirolimus for the second cohort of 19 patients. Forty patients, 22 males (55%) and 18 females (45%) with a median age of 48 years (range 19–64 years) were treated. The diagnoses were AML (n=14), ALL (n=1), NHL (n=10), CLL (n=2), MDS (n=5), Hodgkins Disease (n=5), aplastic anemia (n=2), and chronic myelogeneous leukemia (n=1). Thirty-five patients have greater than 100 days of follow-up and are included in this analysis. The cell doses infused were a median of 4.0 x 10 7NC/kg (range 3.0–6.7 x 107) and 1.9 x 10 5 CD34+ cells/kg (range 0.5–10.0 x 105). Two patients (both with MDS complicating aplastic anemia) experienced primary graft failure, and received second cord blood transplants using a different conditioning regimen. Among the remaining patients, the median time to an absolute neutrophil count &gt;500 was 21 days (range 14–70 days). There were two late graft failures. The median time to a platelet count &gt;20,000 unsupported was 43 days (range 21–125 days). The incidence of acute GVHD Grades II–IV was 40% for the patients receiving cyclosporine/MMF and 29% for patients receiving tacrolimus and sirolimus. There were no deaths from acute GVHD in the cyclosporine/MMF group and one death from acute GVHD in the tacrolimus/sirolimus group. Seven patients (20%) developed chronic GVHD. The 100-day transplant related mortality was 14%. Two deaths were related to Epstein Barr virus related lymphoproliferative disorder, and the other deaths were due to a CNS bleed, staphylococcal sepsis, and respiratory failure due to aspergillus infection. Two patients have relapsed and one has progressive disease. With a median follow up of 14 months (range 3–31 months) the overall survival is 74% and the disease-free survival is 67%. Chimerism analysis showed predominance of one cord by Day +100. In 71% of patients, the first cord blood unit infused predominated. In conclusion, engraftment of adult patients appears to be acceptable using double cord blood products and reduced intensity, non TBI conditioning regimen; the risk of serious acute and chronic GVHD is low, survival is excellent in a selected group of patients and relapse rate is low, suggesting preservation of graft versus leukemia effect despite the low T cell dose.

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