scholarly journals Early engraftment and full-donor chimerism after single-cord blood plus third-party donor dual transplantation in patients with high-risk acute leukemia

2013 ◽  
Vol 49 (1) ◽  
pp. 145-147 ◽  
Author(s):  
I Sánchez-Ortega ◽  
M Arnan ◽  
B Patiño ◽  
M J Herrero ◽  
S Querol ◽  
...  
Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2582-2582 ◽  
Author(s):  
Cori M. Abikoff ◽  
Julie-An Talano ◽  
Carolyn A. Keever-Taylor ◽  
Mark C. Walters ◽  
Shalini Shenoy ◽  
...  

Abstract Allogeneic stem cell transplantation (AlloSCT) from HLA-matched unaffected sibling donors (MSD) has been successful for high-risk SCD, and is the only known curative therapy (Freed/Cairo et al, BMT, 2012). We have recently demonstrated 100% event free survival and absence of sickle cell symptoms following reduced toxicity conditioning and HLA matched sibling bone marrow or cord blood AlloSCT (Bhatia/Cairo et al, BMT, 2014). However, 5 out of 6 children who might benefit from this therapy lack an HLA matched family donor. Identifiable matched unrelated adult donors (URD) in this ethnic group are extremely limited and results from unrelated cord blood transplants are poor (Radhakrishnan K/Cairo et al., BBMT 2013, Kamani et al., BBMT, 2012). We previously demonstrated the use of positive CD34 selection followed by T cell add back (2 x 105 CD3/kg) from unrelated donors in pediatric recipients with both malignant and nonmalignant disease lead to 100% engraftment with minimal acute GVHD (aGVHD). In a high-risk FHI TCD thalassemia study, 16/22 cases engrafted without aGVHD and with 90% overall survival (Sodani et al., Blood, 2010). FHI TCD AlloSCT could expand the donor pool and improve outcomes for patients with high risk SCD. This SCD consortium trial is investigating the safety, feasibility, EFS, donor chimerism, graft failure, aGVHD and chronic GVHD (cGVHD), and infectious mortality after FHI TCD AlloSCT in high-risk SCD patients (Figure 1). High risk features included one or more of the following: ≥1 CVA, ≥2 ACS, ≥3 VOC in past 2 years, or 2 abnormal TCDs. Patients (2-20.99 yrs) without an 8/8 HLA MSD or URD and who have ≥1 high-risk SCD features were eligible. Patients received hydroxyurea 60 mg/kg/d and azathioprine 3mg/kg/d, day -59 – day -11, fludarabine (30mg/m2/d x5d), busulfan (3.2 mg/kg/d x4d [<4yrs of age: 4 mg/kg/d x4d]), thiotepa (10 mg/kg/d x1d), cyclophosphamide (50mg/kg/d x4d), R-ATG (2mg/kg/d x4d), and TLI (500cGy) followed by FHI T-cell depleted AlloSCT. AGVHD prophylaxis included tacrolimus single agent. We utilized the CliniMACS (IND 14359) to enrich for peripheral blood hematopoietic progenitor cells (HPC's); target dose of 10 x 106 CD34+ cells/kg with 2 x 105 CD3+ T cells/kg added back as a final CD3/kg concentration. Six patients have received AlloSCT to date (Figure 2). All patients utilized maternal donors who encountered no complications during collection. All had early neutrophil engraftment (median day +9), ≥98% whole blood chimerism and ≥85% RBC donor chimerism, no aGVHD or cGVHD (Figure 2). One patient developed late hepatic SOS and died at day +59; the remainder are alive and free of disease (day +12 to +642). One more patient has been enrolled and has begun conditioning and others are in the early part of their transplant process. Early results indicate FHI TCD AlloSCT is feasible in high-risk SCD patients who lack a MSD or URD. A larger cohort with longer term follow-up is needed to assess long-term safety and outcomes (Supported by FDA 5R01FD004090 and a grant from Otsuka) (IND #14359 and NCT 01461837). http://www.sicklecelltransplantconsortium.org Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3240-3240
Author(s):  
J. Rafael Cabrera ◽  
Isabel Krsnik ◽  
Rafael Fores ◽  
Elena Ruiz ◽  
Guiomar Bautista ◽  
...  

Abstract We have co-infused mobilized purified hematopoietic stem cells (HSC) from a third party donor to shorten neutropenia in single unit cord blood transplantation (CBT). We describe post-engraftment infectious complications in 33 consecutive adults with high-risk hematologic malignancies. Median age was 30 (range 16–59), 22 were male. Patients were conditioned with TBI or busulfan, fludarabine, cyclophosphamide and ATG. GVHD prophylaxis included CyA and steroids. Non-bacterial prophylaxis included fluconazol, acyclovir, trimethoprim-sulfamethoxazole and azithromycin or Fansidar (toxopositive cases). Median total infused CB cell dose was 2.26 x 107/kg (1.31–3.7). Pre-CBT toxoplasma serology was positive in 12, negative in 13 (4 received HSC from a seropositive donor) and unknown in 8 cases. Pre-CBT CMV serology was positive in 30 cases. Pre-CBT, 7 patients were HBsAb(+), HBsAg(−) and 1 HBsAg(+) HBsAb(−). ANC&gt;500/uL was achieved by 32/33, median time 10 days (9–36). Full CB chimerism was achieved in 32/33 cases. Most clinically significant infections occurred after ANC recovery (no major neutropenic infections).There were 34 episodes of CMV reactivation (3 patients developed CMV peumonitis and died &lt;+60).Three patients developed CNS toxoplasmosis (2 seropositive pre-CBT): 1 died as a result (day +70); 1 died of acute GVHD (+120); 1 is alive on Fansidar (+547). One patient had visceral leishmaniasis (day +180) (BM aspirate for FUO; alive on amphotericin, day +379). Seven patients developed hemorrhagic cystitis, 6 related to polyomavirus (PCR on urine): 4 resolved without specific treatment and 2 with treatment (cidofovir, leflunomide). One had asymptomatic viruria. Reappearance of HBsAg occurred in 3/7 of the HBsAb (+) HBsAg(–) patients after day 100: 1 asymptomatic, 1 acute hepatitis and 1 cirrhosis. A HBsAg(+) patient was transplanted on adefovir (no increase in the viral load or liver enzymes). Four late (≥120) episodes of HZV were seen. A 27-year-old native Spaniard died (day +39) of tripanosomiasis (BM aspirate for FUO, positive PCR). Activation of pre-CBT transfusion-related infection is suspected. Short and long term results in adult CBT are improving. However we and others are reporting high incidence of post-engraftment unusual infections which seem related to delayed recovery of cell-mediated immunity. CMV, for which early diagnostic techniques and antiviral agents are available, heads the list. Our toxoplasma cases have prompted us to use prophylaxis in seropositive patients. HBV reactivation among HBsAb(+) HBsAg(−) patients raises the issue of prophylaxis during CBT versus close serological monitoring and pre-emptive therapy. Leishmaniasis is endemic among our city’s dogs, so we actively search for it in FUO (BM examination and culture). Polyomavirus can be found in the urine of up to 50% of BM recipients, viruria preceding symptoms. The value of prospective monitoring and the role of antivirals are unknown. Other unusual infections (as tripanosomiasis in our country) require high index of awareness and consideration in FUO protocols (BM, PB smears). Adult CB recipients are at very high risk of fastidious non-bacterial infections requiring wide pre-BMT screening, close analytical and clinical monitoring, prophylactic/preemptive strategies or early aggressive therapy and innovative immunotherapeutic approaches.


Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5457-5457 ◽  
Author(s):  
Wieslaw Wiktor-Jedrzejczak ◽  
Malgorzata Rokicka ◽  
Elzbieta Urbanowska ◽  
Tigran Torosjan ◽  
Anna Gronkowska ◽  
...  

Abstract Adult patients with high risk acute leukemia have allogeneic hematopoietic transplantation as the only therapeutic option with some curative potential. Those who lack related or unrelated marrow donor are deprived of this possibility. Patients of smaller size may benefit from the transplantation of single cord blood unit, but for heavier patients two units may be required as reported by Barker et al. (Blood2005;105:1343). For very heavy patients even more units would be necessary to approximate the preferred threshold of 37 millions of cells per kilo. Moreover, cord blood units have variable size and it is always a risk that the only HLA-matched units for given patients would be small and two units would not provide adequate number of cells even for patients of moderate size. This is yet another argument to attempt transplantation of more than two units. Three patients have so far been included. Patient No 1 was 24 yrs old male (body weight 87 kg) with resistant AML transplanted with 3 units (two matched at 4/6 HLA antigens, one matched at 3/6 HLA antigens) on March 29, 2004 following conditioning with standard BuCy4 + ATG regimen. This patient died d. +42 of Gram negative sepsis without hematopoietic reconstitution. Patient No 2 is 22 yrs old male (body weight 100 kg) with Ph+ ALL in complete remission, who was transplanted on October 11, 2004 with 3 units (two matched at 4/6 HLA antigens, one matched at 3/6 antigens) following conditioning with TBI, etoposide and ATG. This patient had neutrophil recovery d. +27, and platelet recovery d. +49. He is alive and well 9 months after the transplant fully chimeric with progeny of only one of transplanted units. Patient No 3 is 31 yrs old male (body weight of 100 kg) with ALL relapsed after autologous BMT with multiple cytogenetic abnormalities. He was transplanted May 24, 2005 with 3 units (one matched at 5/6 HLA antigens, two matched at 4/6 HLA antigens) following conditioning with treosulfan, cyclophosphamide, melphalan and ATG (he earlier received TBI prior auto-BMT). Patient obtained neutrophil recovery d. +36 and as of d.+60 still has low platelets. No data on chimerism are yet available. These data confirm that transplantation of more than two cord blood units is feasible and may provide therapeutic option for patients with high risk leukemia who lack marrow donor and for whom two cord blood units do not provide sufficient number of cells. As in the case of the transplantation of two units patients seem to be reconstituted with progeny of only one “winning” unit.


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4547-4547
Author(s):  
Olga Pérez ◽  
Manuela Aguilar ◽  
Almudena Martín ◽  
Jose Falantes ◽  
Isabel Montero ◽  
...  

Abstract Abstract 4547 Background Fungal infections remain a vital threat to the immunocompromised patient. Due to the high mortality rate of invasive mycoses, antifungal prophylaxis and prevention appear appropriate in some settings. Patients (pts) with prolonged and severe neutropenia or recipients of allogeneic hematopoietic stem cell transplantation (HSCT) appear to be at high risk for filamentous fungal infections, which are associated with low survival rates. However, there is no consensus on the optimal prophylaxis, eligible patients or its effectiveness and clinical impact. Objective To analyze the need for antifungal prophylaxis in Acute Leukemia patients receiving chemotherapy and the effectiveness of fluconazol, followed by posaconazol if GVHD developed, in recipients of allo-HSCT as antifungal prophylaxis. Methods and patients Period: from june’07 through june’09. Acute leukemia adult patients receiving chemotherapy as induction or re-induction therapy did not received primary antifungal prophylaxis. Recipientes of Allo-HSCT received 400 mg/d of fluconazole until discharge followed by 200 mg/8h of posaconazole if graft-versus-host disease (GVHD) developed, until its resolution. Patients received secondary antifungal prophylaxis according to their IFI. There were 77 pts who presented 218 episodes of post-chemotherapy neutropenia (80 in ALL and 138 in AML), 207 received no antifungal prophylaxis. On the other hand, we analyzed 40 consecutive Allo-HSCT adult recipients with an average age of 39 years (15-65) followed as in-patient and out-patient basis during a mean period of 18 months (3-24). Standard myeloablative or reduced intensity conditioning schemes were used and donors were HLA-identical sibling (27), unrelated donor (8) and umbilical cord blood (5). Diagnoses: AML (21), ALL (10), NHL (3), MDS (2), CML (2), HL (1) and AAS (1). The GVHD prophylaxis was according to standard protocols with MTX and CsP/MMF or standard umbilical cord blood protocols. Non-normal distribution data were expressed as median values (range). Chi-square test or Fisher exact test were used to compare differences between groups of categorical data. Differences were considered statistically significant for p-values < 0.05. All statistical analyses were performed using SPSS 16.0 software (Chicago, IL). Results Acute leukemia patients: There were 8 proved or probable fungal infections (EORTC/MSG consensus), with an incidence of 3.6%. The incidence of IFI in the whole induction AML group was 2.4%, (6.9% in the consolidation AML group, 25% in the re-induction AML group) and 5.2% in induction LLA and no case (0%) in the re-induction ALL group. As etiology, Aspergillus Fumigatus (1), Aspergillus spp (4), Candida tropicalis (1) and Candida spp (2). There were 3 deaths caused by IFI (37.5% of IFI); two of them in the re-induction AML group. Allogenic hematopoietic stem cell transplantation recipients: 33 patients received fluconazole (82.5%) and 4 pts (10%) fluconazole followed by posaconazole. Other 3 received posaconazole (2) or voriconazole 200 mg/12 hours (1) as secondary prophylaxis since the conditioning. There were 7 cases of IFI (incidence of 17.5%), 3 proved IFIs and 4 probable IFIs. As etiology, Aspergillus Fumigatus (2), Aspergillus spp (4) and Candida albicans (1). Six patients had received fluconazole and one (candidiasis), fluconazole and posaconazole. The mortality attributable to IFI were 4 cases (57% of IFI). There was no IFI in the group of 9 pts without GVHD and all IFIs occurred in patients treated for GVHD. Conclusions 1) Patients in re-induction of AML may require an effective prophylaxis against fungal infections, but not AML during induction or ALL in any situation. 2) The prophylaxis regimen studied in allogenic HSCT recipients was effective in preventing IFIs in patients without GVHD but not in patients with GVHD, particularly in the case of filamentous fungi. 3) The overall incidence of IFI in allo-HSCT was similar to that reported in other series of high risk and mortality from IFI similar to that described in recent years. 4) Patients with GVHD require more effective antifungal prophylaxis regimens and are candidates for clinical trials. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2588-2588
Author(s):  
Doris M. Ponce ◽  
Patrick Hilden ◽  
Sean M. Devlin ◽  
Molly Maloy ◽  
Marissa N Lubin ◽  
...  

Abstract Background: Double-unit cord blood transplantation (DCB-T) is a rapidly available alternative to unrelated donor transplantation (URD-T) for patients with high-risk acute leukemia or advanced CML. Retrospective analyses in adult DCB-T suggest that double-unit CB grafts may be associated with improved disease-free survival (DFS). However, the prioritization of URD-T vs DCB-T is controversial. Methods: We evaluated 175 consecutive adult allograft recipients (120 URD-T and 55 DCB-T) aged 16-60 years transplanted 10/2005-11/2012 for acute leukemia in morphologic remission or aplasia (113 AML/ biphenotypic, 50 ALL), or advanced CML (n = 12). URD grafts were 7-8/8 HLA-matched (74 8/8, 46 7/8). CB grafts were 4-6/6 donor-recipient HLA-matched (4 6/6, 51 5/6, 55 4/6). All patients received either high dose or reduced intensity myeloablative conditioning. The majority of URD-T recipients (n = 111, 93%) received T-cell depleted (TCD) grafts with rabbit ATG, whereas GVHD prophylaxis for DCB-T was calcineurin-inhibitor/mycophenolate mofetil. Results: The median ages of URD-T (43 years) and DCB-T (42 years) recipients were similar (p = 0.713). Distributions of gender, recipient CMV positivity, HCT-CI scores, time from diagnosis or relapse to transplant, diagnoses, disease risk, and percentage of patients with minimal residual disease pre-transplant were also similar. Neutrophil engraftment was slower in DCB-T (95%, median 24 days) than URD-T (100%, median 11 days) (p <0.001). While the incidence of grade II-IV acute GVHD at day 100 was lower in TCD URD-T recipients (15%) than in unmodified URD-T (56%) and DCB-T (55%), p = 0.002, the incidence of day 100 grade III-IV acute GVHD was similar in TCD URD-T, unmodified URD-T, and DCB-T recipients (p = 0.794). With a comparable survivor follow-up [URD-T median 51 months (range 15-99) vs DCB-T median 46 months (range 15-92)], transplant-related mortality was similar (3-year estimates: URD-T 25% vs DCB-T 24%, p = 0.838) whereas the relapse risk was decreased after DCB-T (3-year estimates: URD-T 23% vs DCB-T 9%, p = 0.008). Overall, the 3-year DFS after URD-T was 52% and 68% after DCB-T (p = 0.056). When split into 3 groups, the 3-year DFS was 59% in 8/8 URD-T, 40% in 7/8 URD-T, and 68% in DCB-T, p = 0.043 (Figure). Multivariate analysis was performed to determine risk factors for disease relapse or death in the 175 patients (Table). Female gender (HR 1.65, p = 0.029), diagnosis of ALL (HR 2.11, p = 0.002), and mismatched URD-T (HR 1.97, p = 0.027) were each significantly associated with treatment failure. Conclusions: DCB-T can achieve favorable DFS in adults with acute leukemia and CML with low relapse rates. In this series, multivariate analysis demonstrated that mismatched URD-T was independently associated with lower DFS. Our findings support use of DCB-T as an immediate alternative for high-risk acute leukemia and advanced CML in adult patients without a readily available 8/8 allele HLA-matched unrelated volunteer donor. This could have the additional benefit of speeding time to transplant in high-risk patients. Table Variable MultivariateHR (95% CI) P-value Male Female Reference 1.65 (1.05-2.59) 0.029 Recipient CMV Negative Recipient CMV Positive Reference 1.34 (0.85-2.12) 0.201 HCT-CI score 0-2 HCT-CI score > 3 Reference 1.56 (0.98-2.47) 0.059 AML/CML ALL Reference 2.11 (1.30-3.41) 0.002 DCB-T 8/8 URD-T 7/8 URD-T Reference 1.32 (0.72-2.41) 1.97 (1.08-3.60) - 0.365 0.027 Figure Figure. Disclosures No relevant conflicts of interest to declare.


2013 ◽  
Vol 5 (1) ◽  
pp. e2013029
Author(s):  
Giuseppe Visani ◽  
Paola Picardi ◽  
Barbara Guiduccu ◽  
Claudio Giardini ◽  
Moira Lucesole ◽  
...  

A 9-year-old female received a double allogeneic stem cell transplant (SCT) from an ABO-incompatible HLA-matched sibling for β-thalassemia major, without achieving a complete donor chimerism. Subsequently, the patient received autologous SCT and five donor lymphocyte infusion, without increasing donor chimerism. After the double transplant failure, we performed an unrelated transplant from a full-matched umbilical cord blood (UCBT). Due to the severe immunosuppression of the patient, we did not administer any conditioning regimen nor GVHD prophylaxis. On day +40 after UCBT, trilinear engraftment was documented. Surprisingly, the hematopoietic reconstitution was related to the re-expansion of the autologous (β-thalassemic) hematopoietic stem cell, as documented by chimerism studies on both peripheral blood and bone marrow. At present, 30 months after UCBT, there is stable hematopoietic autologous reconstitution. This is the first description of the restoration of autologous hematopoiesis obtained with cord blood infusion in a thalassemia-major patient after a double transplant failure.


Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3401-3401 ◽  
Author(s):  
Mi Kwon ◽  
Jurgen H Kuball ◽  
Pauline Ellerbroek ◽  
Pascual Balsalobre ◽  
David Serrano ◽  
...  

Abstract Background The safety and usefulness of unrelated umbilical cord blood (CB) stem cell transplantation (SCT) in patients candidates for allogeneic SCT and HIV infection is unknown. Single CB with the co-infusion of CD34+ cells from a third party HLA-mismatched donor (TPD), or Haplo-cord SCT, has shown to reduce the period of post-transplant neutropenia and related early complications associated with single CB transplantation. This platform could potentially reduce the risk of early infections in this particular group of patients. On the other hand, the use of a cell source homozygous for the CCR5 delta32 allele mutation, which confers high resistance against HIV-1 acquisition, is of particular interest in HIV+ patients. Methods and Results We report here on the first two patients with HIV infection and high-risk haematological malignancies who underwent haplo-cord SCT in two different centers: (Case 1) a 53 year-old male patient with high-risk MDS; (Case 2) a 34 year-old male with Burkitt lymphoma in CR2. Both CB transplants were performed using the haplo-cord platform with the co-infusion of mobilized and selected CD34+ cells from a TPD. Conditioning regimen were myeloablative in both cases. Case 1 had the additional potential benefit from the use of a CB unit with the homozygous CCR5delta32 mutation. Both cases achieved neutrophil and platelet engraftment similarly to previous haplo-cord SCT performed in HIV negative patients, as well as full CB chimerism. However, case 1 developed beside a severe lung infection, relapse of the underlying malignancy 2 months after SCT and died consequently. Case 2 presented one episode of bacterial sepsis with good response to antibiotics, and one episode of CMV reactivation controlled with valgancyclovir. Thirteen months after SCT, this patient is alive and in CR. Extensive analyses of viral and immunological compartments were performed showing the early viral dynamics in both patients. Conclusions CB SCT is feasible in patients eligible for allogeneic SCT and HIV infection. The haplo-cord strategy with the co-infusion of auxiliary cells from a TPD seems to offer a fast neutrophil engraftment similarly to HIV negative patients. Therefore, this strategy should be considered in patients with HIV infection and indication for allogeneic SCT, whenever CB is the source of choice and especially if a CCR5 mutated unit is available. Disclosures: Kuball: Miltenyi: GMP product development Other.


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