Are Back-Up Bone Marrow Harvests of Value in Unrelated Donor Allogeneic Transplants?.

Abstract In June 2007 four members of the University of Michigan Cardiothoracic transplant team died in a plane crash while transporting organs to an expectant transplant recipient. Matched Unrelated Donor Stem Cell transplants (MUDs) require that patients receive the preparative regimen before the hematopoeitic stem cells are transported. Our transplant program performs a “back-up” autologous harvest prior to administration of the conditioning regimen for use if the donor graft fails to arrive or if graft failure occurs. However, this practice is not uniform and insurers sometimes balk at payment. To evaluate the value of their routine collection, we reviewed the results of our center’s use of back-up marrows. 215 MUD transplants were performed at CCF from 1/95 to 12/05 and 146 recipients underwent back-up marrow collection. All recipients of adult MUD or Cord Blood transplants with hematologic malignancies in complete remission were harvested. Of 146 back-up marrows harvested, 15 patients (10%) had their back-up harvest infused. All 15 patients received their rescue marrow infusion for graft failure (adult MUD, n=12; Cord, n=3) 0.7–7.6 (median 1.1) months after the original transplant. Seven of the 15 (46%) patients had undergone full molecular matching, the other 8 (54%) patients being matched by serology for class I antigens and DNA typing for class II antigens. 9 patients were 6/6 serologic or molecular matches, 3 patients were 5/6 matches, and the 3 cord transplants were 4–5/6 matches. Deteriorating clinical status and a need for rapid engraftment was the rationale for infusion of autologous back-up marrow, as opposed to seeking additional donor cells (which potentially takes several weeks). Five patients (33%) are alive and in complete remission 14.6 to 137 (median 91) months from back-up infusion. Of these, two were bridged to a second MUD transplant. These two patients are alive and well at days 4200 and 1950 respectively. The other three have shown surprisingly durable disease free survival without repeat allogeneic transplant. Survivors Following Rescue Autologous Stem Cell Infusion Patient No. Primary Disease Transplant Material - all MUD Day of rescue infusion HLA typing of 1st transplant Second transplant Outcome 1 CML BM +29 Serologic 6/6 Yes (+560) Alive last f/u (+4200) 2 CML BM +33 Serologic 5/6 No Alive last f/u (+3363) 3 NHL BM +62 Serologic 8/8 No Alive last f/u (+2833) 4 AML Adult PBSC +230 Molecular 8/8 Yes (+1581) Alive and well (+1950) 5 AML Cord +38 Molecular 5/6 No Alive last f/u (+482) In total, 5 patients went on to a second transplant, all from adult MUD donors. Three patients died following second transplant - two from relapse and the 3rd from ARDS. Ten patients died following back-up infusion: 4 (36%) from relapse, 5 (54%) from infections and 1 from graft failure before rescue cells could engraft. Within this group, patients lived a mean of 114.5 (4–357) days from autologous rescue. Five patients were discharged from the hospital and lived a mean of 7.1 (1–12) months from discharge. In conclusion, a rescue autograft following graft failure may allow for rapid hematopoeitic recovery providing an opportunity for a second allogeneic transplant if another donor is available. In some cases it can directly result in durable remission. This procedure has saved the lives of 5 patients and should be more widely employed.

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

Blood ◽

10.1182/blood.v108.11.320.320 ◽

2006 ◽

Vol 108 (11) ◽

pp. 320-320 ◽

Cited By ~ 2

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.

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Efficacy of Reduced-Intensity Allogeneic Stem Cell Transplant after Brentuximab Vedotin in Patients with Hodgkin Lymphoma Relapsed after Autologous Transplant

Blood ◽

10.1182/blood.v124.21.5943.5943 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5943-5943

Author(s):

Francesco Zallio ◽

Alessandro Busca ◽

Nicola Mordini ◽

Maria jose Fornaro ◽

Benedetto Bruno ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Complete Remission ◽

Conditioning Regimen ◽

Brentuximab Vedotin ◽

The Other ◽

Survival Outcomes ◽

Allogeneic Transplant ◽

Reduced Intensity

Abstract Purpose: The prognosis of patients with Hodgkin lymphoma (HL) who relapse following autologous stem cell transplantation (ASCT) is generally poor, because salvage chemo-radiotherapy is able to produce only short-lasting remissions. In a previous study on a large patients' population (Sarina B et al, Blood 2010) was clearly demonstrated that the availability of a donor could significantly improve survival outcomes after allogeneic transplant, in particular for the subset of patients who reach a status of pre-transplant complete remission; however the application of this procedure is actually limited by a difficulty to obtain an objective response before alloSCT. It was recently shown that Brentuximab vedotin, a new generation antibody-drug conjugate, is able to induce nearly 30% of complete remission in HL patients relapsing after autologous transplant; therefore this agent could effectively work in relapses after ASCT as a platform to allow a better disease control in order to improve the outcome of the allografting procedure. Aims: Aim of this study was to retrospectively investigate if brentuximab vedotin administered as a salvage therapy in HL patients relapsing after ASCT could improve the efficacy of a subsequent reduced-intensity allogeneic transplant. Methods: Between August 2011 and September 2013, 11 patients underwent to allo-SCT at four hematologic Divisions of Northern Italy for HL relapse after ASCT, after brentuximab vedotin administered as a bridge to the allografting procedure. Median age was 32 years (range 21-61) and median number of prior regimens was 5, including ASCT. Patients received a median of 6 cycles (range 4-7) of brentuximab vedotin administered every 3 weeks as a 30-minute outpatient IV infusion; median time between the last dose of brentuximab vedotin and the allo-SCT was 1 month (range 1-5 months). No patient experienced progression during treatment with brentuximab vedotin (4 complete remissions and 7 partial remission/stable disease). All but one patients did not have a HLA identical sibling, so they required a matched unrelated (6 patients), haploidentical donor (3 patients) or cord blood (1 patient); peripheral stem cells were the source in patients with HLA identical sibling or unrelated, whereas bone marrow was used in the haplo setting. Reduced-intensity was the conditioning regimen performed in all patients. Post transplant cyclophosphamide plus mycophenolate mofetil/tacrolimus was the graft-versus-host disease (GVHD) prophylaxis of the haplo setting, while Metotrexate/cyclosporine was administered in the other patients. Patients were monitored for engraftment and infectious complications per institutional standards; survival outcomes were defined according to the European Blood and Marrow Transplantation (EBMT) criteria for survival analysis. Results: One patient had primary graft failure with autologous reconstitution; she was a patient with a high body-mass index, in whom the drug's doses of the conditioning regimen were underestimated in order to avoid excessive toxicity. All the other patients engrafted; median time to neutrophil recovery was 20 days (range 15-26). At a median follow-up of 12 months, the 2-year progression free survival was 51%, 2-year Overall Survival was 61%. There were 2 toxic deaths, one for EBV reactivation and one for leuko-encefalopathy disease, resulting in a 2-year non-relapse mortality of 18%. Conclusions: These data suggest that brentuximab vedotin represents a promising salvage therapy in HL patients relapsed after ASCT. Despite the bias concerning the differences in source of stem cells and pre-transplant conditioning regimens, we showed that brentuximab could be administered in patients who are candidates to a RIC allo-SCT, with encouraging survival outcomes. Further clinical trials with larger number of patients and longer follow-up are recommended to confirm the promising role of brentuximab as a bridge to alloSCT. Disclosures No relevant conflicts of interest to declare.

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Mismatch at 1-2 HLA Loci Does Not Reduce Survival Following Alemtuzumab-Based Reduced Intensity Unrelated Donor Allogeneic Transplantation

Blood ◽

10.1182/blood.v112.11.3008.3008 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3008-3008

Author(s):

Adam J Mead ◽

Kirsty J Thomson ◽

Emma C Morris ◽

Ronjon Chakraverty ◽

David C. Linch ◽

...

Keyword(s):

Stem Cell ◽

Molecular Typing ◽

Graft Failure ◽

Chronic Gvhd ◽

Significant Trend ◽

Hla Typing ◽

Mixed Chimerism ◽

Unrelated Donor ◽

Significant Difference ◽

Reduced Intensity

Abstract Most candidates for reduced-intensity allogeneic stem cell transplantation (RIC) do not have a human leukocyte antigen (HLA)-matched sibling donor available. Improved HLA-typing techniques allow more stringent matching of unrelated donors (UD), but have reduced the likelihood of identifying a fully matched UD (MUD), defined as a 10/10 locus match by molecular typing. Whilst donors matching at 8–9/10 HLA loci (MMUD) are considered appropriate by some groups, it is unclear the degree to which HLA-mismatch increases procedural toxicity and how this is influenced by different regimens. Availability of alternative stem cell sources such as umbilical cord blood makes it important to clearly define such risks. We therefore analyzed outcomes of 99 consecutive patients who underwent RIC using an UD in our institution from October 1998 to July 2008. Donor selection was performed according to standard criteria, including molecular typing for HLA-A, -B, -C, DRB1 and DQB1. Donors were 10/10 HLA-matched (n=62) or mismatched at up to 2 HLA loci (n=37). Conditioning was 20mg/d alemtuzumab for 5 days, fludarabine 30mg/m2 for 5 days and melphalan 140mg/m2 for 1 day, with cyclosporine from day -1. Peripheral blood stem cells were used in 51 (30 MUD, 21 MMUD) and bone marrow in 48 (32 MUD, 16 MMUD). Median age was 47 years (13– 67), and underlying disease was AML (n=9), myeloma (n=13), Hodgkin (n=18) or non- Hodgkin lymphoma (n=40), and others (n=19). Patients had a median of 4 previous lines of treatment (0–9) and 49 had failed a prior autograft. There were no significant differences between the groups in terms of age, sex, prior autograft, number of treatment lines, or chemosensitivity at transplantation. There were significantly more CMV seropositive recipients in the MMUD group (P.002). Neutrophil recovery (>0.5 × 109/l) occurred at a median of 12 days (9–57) and did not differ between MUD and MMUD (median 11 vs 12 days). Two patients, both MUDs, had primary graft failure and engrafted following CD34 top-up. Three patients rejected the graft, all MMUDs (P.07 for MUD vs MMUD). Secondary graft failure occurred in 3 cases, all MMUDs (P.07 for MUD vs MMUD). All 3 received CD34 top-up with subsequent improvement in counts in one, another died shortly after infusion of cells and 1 remains cytopenic 4 years following the transplant. Of 40 at risk cases, CMV reactivation requiring treatment occurred in 35 (88%; 85% MUD and 90% MMUD). Donor lymphocyte infusions (DLI) were administered in 35 cases, 23 for disease relapse and 12 for mixed chimerism alone, with no significant difference between MUD (n=25, 40%) and MMUD (n=10, 27%, P.4). There was no difference in the incidence of grade 2–4 acute graft-versus-host disease (aGvHD) between MUD (27%) and MMUD (30%, P.7). Prior to DLI, only 3 cases of grade 3 aGvHD occurred (2 MUD and 1 MMUD) and no grade 4 aGvHD. Chronic GvHD (cGvHD) at 1 year occurred in 30%, with a non-significant trend for a lower incidence in MUD versus MMUD patients (24% vs 40%, P.1). Extensive cGvHD at 1 year was 15% (MUD 13% and MMUD 18%, P.6) excluding post-DLI GvHD, and was 26% at 1 year (MUD 26% and MMUD 27%, P.4) and 40% at 3 years (MUD 34% and MMUD 46%) including post-DLI GvHD. With a median follow-up of 3.0 years, transplant related mortality (TRM) for the whole cohort was 14% at 100 days and 28% at 1 year, with no significant difference between MUD (13% and 30%) and MMUD (16% and 27%). Overall survival (OS) at 3 years was 46% for the whole cohort (45% for MUD, 48% for MMUD). The outcome of 1 (n=20) versus 2 (n=17) locus mismatched transplants was also compared. There was a non-significant trend to increased grade 2–4 aGvHD (16% versus 39%, P.2) in the 2 locus MMUD group but extensive cGvHD (including post-DLI GvHD) at 1 year was not different (30% vs 24%, P.6). Survival was not inferior in the 2 locus MMUD group relative to the single mismatches, with 100 day TRM (20% 1 locus vs 13% 2 locus, P.5), 1-year TRM (43% 1 locus vs 19% 2 locus, P.5), and 3 year OS (32% 1 locus vs 63% 2 locus, P.3). We conclude that 8–9/10 MMUD-RIC is a viable option using T-cell depletion with 100mg alemtuzumab in vivo, without a significant adverse impact on TRM or OS compared with 10/10 MUD. The long-term OS of 48% following MMUD-RIC is encouraging given the inclusion mainly of patients with multiply relapsed/refractory hematological malignancy.

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Busulfan Dosing May Affect Survival Following Reduced Intensity Stem Cell Transplantation in Patients with Acute Myelogeneous Leukemia.

Blood ◽

10.1182/blood.v114.22.4328.4328 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4328-4328

Author(s):

Karen K Ballen ◽

Steven L McAfee ◽

Bimalangshu R Dey ◽

Christine Dube ◽

Eyal C Attar ◽

...

Keyword(s):

Stem Cell ◽

Complete Remission ◽

Total Dose ◽

Conditioning Regimen ◽

Allogeneic Transplantation ◽

Unrelated Donor ◽

Gvhd Prophylaxis ◽

Acute Myelogeneous Leukemia ◽

Reduced Intensity

Abstract Abstract 4328 The prognosis for patients with acute myelogeneous leukemia over age 60 is poor, with a 5 year survival of less than 10%. Reduced intensity allogeneic transplantation has been employed in an attempt to improve survival. We report 23 patients who received reduced intensity allogeneic transplantation after a conditioning regimen of busulfan and fludarabine. Fifteen patients received a transplant from a matched sibling donor,1 patient from a 5/6 matched child and 7 patients from a fully matched (10/10) unrelated donor. We treated 10 patients with the reduced intensity conditioning regimen of busulfan IV 0.8 mg/kg daily Days -6, -5, -4, -3 (total dose 3.2 mg/kg) and fludarabine IV 30 mg/m2 Days -6,-5, -4, -3 (total dose 120mg/kg). After November, 2007, 10 patients were treated with twice daily busulfan IV 0.8mg/kg (total dose 6.4 mg/kg) with the same dose of fludarabine. Three patients were treated on a national protocol in which the same dose of busulfan (6. 4 mg/kg) was administered but given at 0.8 mg/kg four times daily for 2 days on Days -4 and -3 with fludarabine. GVHD prophylaxis was cyclosporine or tacrolimus with either cellcept or (after July, 2008) methotrexate. Seven recipients of unrelated donor or mismatched transplants also received rabbit antithymocyte globulin 1.5 mg/kg Days -3, -2, -1 (total dose 4.5 mg/kg) as part of their GVHD prophylaxis. Median age was 65 years (range 46-70 years). Fourteen patients were in 1st complete remission, 8 were in 2nd complete remission, and one patient had active disease at the time of transplant. Two patients had received a prior autologous stem cell transplant and 2 patients had received a prior allogeneic transplant. The median days to neutrophil (ANC >500) and platelet engraftment (plt >20K) were 15 and 14 respectively. The median length of stay was 25 days (range 13-40 days). Median follow-up was 12 months among the 10 patients still alive. The incidence of acute GVHD Grades II-IV and chronic GVHD were 44% and 35% respectively. Transplant related (non relapse) mortality at 100 days and at 6 months was 0. The overall non-relapse mortality was 4%. Relapse rate was 67% in the daily busulfan group and 46% in the higher dose busulfan group. The one-year overall and disease-free survivals for all patients were 44% and 25% respectively. Causes of death were relapse in 12 patients and in one patient sepsis six years after transplant. In multivariate analysis, disease status, age, and GVHD did not predict for survival, perhaps due to the small sample size. There was a trend to improved survival in the higher dose busulfan group but the follow up was shorter for these patients. In summary, 1) Reduced intensity transplantation is tolerated well in an older population with acute myelogeneous leukemia, with no transplant related mortality at Day 100 or at 6 months post transplant; 2) Relapse rermains the most common cause of death; 3) There was a trend to improved survival with a twice daily busulfan dosing. Future studies will address the outcomes of twice daily busulfan dosing in a larger cohort of older patients with AML in complete remission. Disclosures: Spitzer: Genzyme: Consultancy.

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The Use of Etoposide, Ara-Cytarabine, and Melphalan (EAM) Conditioning Chemotherapy in Autologous Stem Cell Transplantation (ASCT) for a Patient with Relapsed Hodgkin’s Lymphoma

Case Reports in Hematology ◽

10.1155/2021/9632427 ◽

2021 ◽

Vol 2021 ◽

pp. 1-6

Author(s):

Eko A. Pangarsa ◽

Ridho M. Naibaho ◽

Vina Yunarvika ◽

Budi Setiawan ◽

Damai Santosa ◽

...

Keyword(s):

Stem Cell ◽

Complete Remission ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Autologous Stem Cell Transplantation ◽

Hodgkin’S Lymphoma ◽

Remission Rate ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Hodgkin's Lymphoma

Up to 20–40% of patients with Hodgkin’s lymphoma will eventually relapse after treatment, among which early relapse confers a poor outcome. With salvage chemotherapy followed by autologous stem cell transplantation (ASCT), the long-term remission rate is 30%. We report our experience of using a modified-BEAM conditioning regimen without BCNU consisting of etoposide, cytarabine, and melphalan (EAM) in a patient with relapsed Hodgkin’s lymphoma. Before transplantation, the patient achieved second complete remission (CR2) using brentuximab vedotin and ESHAP (BR-ESHAP) chemotherapy. The ASCT went well without significant complications. This case demonstrated the considerable efficacy of EAM protocol as a conditioning regimen in terms of sufficient ablative capabilities, and the patient showed a successful hematopoietic engraftment. Although durability of the disease-free survival needs further observation, it had nearly 18 months of complete remission and the patient was in good performance status at the time of writing this manuscript.

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Is Antilymphocyte Globulin Useful in Conditioning Regimen of Unrelated Donor Hematopoïetic Stem Cell Transplantation?.

Blood ◽

10.1182/blood.v106.11.2067.2067 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2067-2067

Author(s):

Helene Esperou ◽

Marie Lorraine Appert ◽

Ibrahim Yacoub Agha ◽

Noel Milpied ◽

Norbert Ifrah ◽

...

Keyword(s):

Stem Cell ◽

Acute Gvhd ◽

Conditioning Regimen ◽

Multivariable Analysis ◽

Hla Typing ◽

Unrelated Donor ◽

Allelic Differences ◽

Group 2 ◽

Grade Iii ◽

Group 1

Abstract Between 1998 and 2004, 2141 allogeneic hematopoietic stem cell transplantations with unrelated donor (excluding cord blood) have been recorded on the SFGM-TC data base. The lack of unique behavior in regard of Anti Lymphocyte Globulin (ALG) use in unrelated donor transplants allowed us to perform a retrospective study to assess the influence of ALG in such grafts. To avoid biaises we excluded T cell depletion or monoclonal antibody use, reduced intensity conditioning and focused only on patients (pts) with acute leukemia (AL) and myelodysplasia (MDS). So we defined a study population of 553 pts. In addition, in order to analyze the actual impact of ALG on wellknown targets (engraftment, acute GvHD, relapse, survival) we choose to keep only the cases in which was available the allelic HLA typing (4 digits) for the recipient and the donor, i.e. 250 pts. There were 106 females and 144 males, allografted in 29 centers. The median age was 23 years (1–62) and there were 77 children under 15. There were 223 AL - myeloid n=120, lymphoid n=103 - and 27 MDS. The source of cells was bone marrow for 190 pts and peripheral mobilized stem cells for 60. One hundred and ninety-three pts received a conditioning regimen including Total Body Irradiation. Ninety-five pts received ALG (mainly Thymoglobulin Mérieux-Genzyme Lyon France at various doses) for a median of 3 days (group 1) and 155 did not (group 2). There were 189 donor/recipient pairs strictly HLA-matched 10/10, 49 with one allelic difference (HLA A n=13; HLA B n=8; HLA C n=13; HLA DRB1 n= 5; HLA DQB1 n=10 ), 11 with 2 allelic differences and 1 with 3 allelic differences. 238 pts have sustained engraftment at a median time of 20 days (9–41) without any influence of ALG use (97% vs 94% NS). Overall survival at 3 years was 45% in group 1 and 52% in group 2 (NS). The incidence of acute GvHD (grade II to IV) was similar in the two groups (59% vs 54%), but the incidence of acute GvHD (grade III to IV) was lower in group 1 (21% vs 32% p=0.03). Use of ALG did not affect rate relapse (18% vs 20% NS). In a multivariable analysis including HLA disparities, patient age, use of ALG, two factors appear as predictive for grade III–IV GvHD: HLA-identity (p=0.05) and use of ALG (p=0.02). These factors are not significant for survival in the same multivariable analysis but in this allelic matched population, the influence of ALG should be analyzed in regard of exact dose of ALG.

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Non-Myeloablative Hematopoietic Transplant with Sirolimus Immunosuppression: Determinants of Outcome.

Blood ◽

10.1182/blood.v106.11.5462.5462 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5462-5462

Author(s):

David F. Claxton ◽

Chuancai Wang ◽

Michelle Carraher ◽

Christopher Ehmann ◽

Witold Rybka

Keyword(s):

Graft Failure ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Unrelated Donor ◽

Logit Analysis ◽

Risk Of Death ◽

Increased Risk ◽

Donor Cells ◽

Alternative Donor ◽

Disease Free

Abstract We added Sirolimus to an established conditioning regimen in an attempt to optimize engraftment and anti-tumor effects while minimizing GVHD. 55 patients patients with advanced hematological malignancies (median age 60) received cyclophosphamide (1gm/m2 days −7 and −6) and fludarabine (25mg/m2 days −7 through −3) prior to peripheral blood cell (51 patients) or marrow (4 patients) transplant. All received sirolimus with tacrolimus, both adjusted to 5–15ng/ml, and methotrexate (5mg/m2 days 1,3, 6) immunoprophyllaxis. Tacrolimus was tapered from days 30–45 in matched siblings (Msib -12 patients) and days 40–100 in (most) alternative donor recipients (AltD- unrelated donor or 5/6 matched related cells - 43 patients) without acute GVHD. Median follow-up is 313 days in AltD patients and 337 days for Msib patients. All Msib cells engrafted, whereas 3/43 AltD recipients showed primary graft failure or secondary graft failure (1/43). Msib recipients engrafted more rapidly than those with AltD transplants (p<0.01). For AltD recipients, the CD34 dose had a positive significant effect on donor engraftment - chimerism (p<0.05 for all points up to D100). Median overall and disease free survival was 287 and 230 days respectively for AltD patients and 303 and 167 days for Msib recipients. Amongst AltD patients, 17/43 survive progression free at D114-1167 (median D416), while in MSib patients only 1/12 survives progression free (p=0.0023 ). Two additional patients are disease free after donor lymphocytes (DLI) or withdrawal of immunosuppression in each group. No patient in the Msib group had transplant related mortality (TRM), but in the AltD group there were nine TRMs, including 7 from GVHD (NS). Multivariate analysis showed CD34 dose and donor types had no significant effect on development of progressive disease (PD). However, in general the odds ratio of any PD decreased exponentially as the level of chimerism increased. For example, at D100 the odds of developing PD decreased by 0.699 times when the level of chimerism increased by 0.1. Multinomial logit analysis showed that compared to GVHD death, the odds ratios for PD death decreased exponentially as the level of chimerism increased. In this series of patients with advanced hematological malignancy, Alternative donor cells provided a higher probability of control of disease, albeit with a trend to higher TRM. Higher CD34 cell doses were associated with improved donor engraftment (chimerism) in AltD recipients. For AltD recipients, risk of PD was reduced by increasing donor chimerism, but increasing chimerism is associated with increased risk of death from GVHD. Efforts to improve control of malignancy via more rapid engraftment of donor cells must be tempered with concern regarding potentially severe GVHD. Figure Figure

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Influence of Glutathione S-Transferase A1 and P1 Polymorphisms on the Outcome of Hematopoietic Stem Cell Transplantation with Busulfan Based Conditioning Regimen In Children.

Blood ◽

10.1182/blood.v116.21.3492.3492 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3492-3492

Author(s):

Ji Won Lee ◽

Hyoung Jin Kang ◽

Yen Ju Yuk ◽

Mi Kyoung Jang ◽

Eun Jong Han ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Graft Failure ◽

Conditioning Regimen ◽

The Other ◽

Glutathione S Transferase ◽

Hematopoietic Stem ◽

Gst Polymorphisms

Abstract Abstract 3492 Introduction: Busulfan has narrow therapeutic range. High exposure is associated with systemic toxicity such as veno-occlusive disease (VOD) while underexposure results in graft failure or relapse. In children, pharmacokinetic variability was found to be high even after the introduction of intravenous busulfan. Busulfan is metabolized via liver through conjugation with glutathione S-transferase (GST) family, and inter-individual variability may be explained by GST polymorphisms. Thus, we investigated the influence of GST polymorphisms on the clinical outcomes of hematopoietic stem cell transplantation (HSCT) with busulfan based conditioning regimen in children. Patients and methods: We studied patients who underwent HSCT at Seoul National University Children's Hospital from November, 2001 to November, 2008. IV busulfan (0.8 mg/kg/dose for patients≥10 kg and 1.1 mg/kg/dose for patients <10 kg, q 6hr for 4 days) was used in combination with cyclophosphamide or fludarabine as conditioning regimen. Etoposide was added for acute lymphocytic leukemia (ALL). GST polymorphisms (GSTA1 375 A > G, -52 G > A, -567 G > T, -631 G > T, -69 C > T, GSTM1 deletion, GSTT1 deletion, and GSTP1 313 A > G) were analyzed by multiplex PCR amplification and SNP genotyping. Results: A total of 70 patients (48 male, 22 female) were analyzed. The diagnoses were ALL in 32, AML in 26, and other diseases in 12 patients. Median age at HSCT was 8.8 years (range 1.0–19.0 years). Bone marrow or peripheral blood stem cell transplantations (BMT/PBSCT) were conducted in 42 patients, and cord blood transplantations (CBT) in 28 patients. Graft failure occurred in 11 (15.7%) patients (1 (2.4%) in BMT/PBSCT, 10 (35.7%) in CBT) and relapse occurred in 15 (21.4%) patients (12 (28.6%) in BMT/PBSCT, 3 (10.7%) in CBT) after HSCT. Patients having GSTA1 *A/*A and GSTP1 313 A/A genotype (N=33) showed higher incidence of graft failure than the others (N=37) (27.3% vs 5.4%, P =.01). Conversely, the incidence of hyperbilirubinemia over grade 3 was significantly lower in the patients with GSTA1 *A/*A and GSTP1 313 A/A genotype than the other patients (6.1% vs 24.3%, P =.05). Event free survival (EFS) of patients with GSTA1 *A/*A and GSTP1 313 A/A genotype was significantly lower than the EFS of the other patients in both BMT/PBSCT and CBT, and the main causes of event were graft failure in CBT and relapse in BMT/PBSCT. Conclusions: In children undergoing HSCT with busulfan based conditioning regimen, GST A1 and P1 polymorphisms seem to have influence on the graft failure, relapse and complications. To confirm our results, further studies about the influence of GST A1 and P1 polymorphisms on the pharmacokinetics of busulfan are needed. Disclosures: No relevant conflicts of interest to declare.

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Pentotstatin/TBI Conditioning Is Well-Tolerated and Permits Engraftment of a Second Allogeneic Stem Cell Transplant Following Primary or Secondary Rejection of an Allogeneic Hematopoietic Stem Graft

Blood ◽

10.1182/blood-2019-122467 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5657-5657

Author(s):

Ani Gvajaia ◽

Amelia Langston ◽

Natia Esiashvil ◽

Michael Graiser ◽

Kelly Valla ◽

...

Keyword(s):

Single Dose ◽

Graft Rejection ◽

Graft Failure ◽

Low Dose ◽

Conditioning Regimen ◽

Unrelated Donor ◽

Allogeneic Transplant ◽

Research Support ◽

Cd34 Cells ◽

Matched Sibling

Introduction: Graft failure remains a major obstacle to the success of allo-HSCT. Rates of graft failure are reported to be 2% in recipients of HLA identical grafts, 9% in those with an unrelated donor, and up to 12.3% in those with an HLA-mismatched related donor (0-3 antigen mismatched). Graft failure is associated with high mortality due to prolonged cytopenia's leading to significant anemia, bleeding, and infection. Successful management of graft failure usually requires a second transplant to restore normal hematopoiesis. The selection of a preparative regimen presents a challenge in these patients who have recently undergone myelosuppressive therapy prior to the failed transplant maneuver. We have employed the use of a minimally myelosuppressive regimen consisting of a single dose of pentostatin with a low dose of total body irradiation (TBI) as conditioning prior to a second allogeneic transplant for patients who experienced primary graft rejection. Methods: Under an IRB-approved retrospective study, we describe 4 consecutive patients with graft failure after allogeneic stem cell transplantation, who received a re-conditioning regimen consisting of pentostatin and low-dose TBI prior to second allo-HSCT. The median age of patients was 38 years (23-51). The conditioning regimens of the first transplant were myeloablative doses of cyclophosphamide/rabbit ATG; busulfan/fludarabine rabbit ATG/; busulfan/fludarabine; and fludarabine/melphalan (Table 1). Median cell doses for the first transplant were 7.7 x 10E6 CD34+ cells/kg and 104 x 10E6 CD3+ cells/kg. Two patients had primary graft rejection and 2 patients had secondary graft rejection. Patients with secondary graft rejection had initial hematopoietic engraftment of neutrophils on a median of 21 days and platelets on a median 61 of days post-transplant with subsequent declines in peripheral blood counts and chimerism studies showing loss of donor cell engraftment. The donor for the second transplant was the same in one patient and different in three patients and included a HLA-matched sibling in 2/4 patients and HLA-matched unrelated donor (URD) in 2/4 patients. One patient had two transplants from the same donor followed by a third transplant from a different HLA matched sibling donor. Conditioning for the second transplant in these cases consisted of pentostatin 4 mg/m2 as a single dose on day -3 and two fractions of 200 cGy TBI on days -2 and -1 as shown in Table 2. Results: Patients underwent the second (or third) donor allogeneic transplant at a median of 99 days following the first transplant. The second donor allograft contained a median of 9.6 x 10E6 CD34+ cells/kg and 390 x 10E6 CD3+ cells/kg. All recipients of the pentostatin-TBI conditioning regimen engrafted following transplantation of allogeneic stem cells (Table 2). Engraftment following the second transplant (or third transplant, in patient #1) occurred at a median of 22 days for neutrophils and 54 days for platelets, and all patients achieved 100% myeloid and lymphoid chimerism. Patients did not experience VOD/SOS or have severe mucositis, enteritis, or pulmonary toxicity, and were hospitalized a median of 39 days from the second transplant. All four patients achieved normal blood counts following the second transplant. One patient died unexpectedly of an apparent infection following full donor hematopoietic reconstitution. Three of the four patients undergoing a second transplant using pentostatin/TBI conditioning are alive without evidence for disease relapse or graft rejection at a median follow-up of 3.5 years, with none of these patients experiencing severe acute or chronic GvHD. Conclusion: Single dose pentostatin combined with low-dose TBI represents an effective and well-tolerated conditioning regimen that facilitates engraftment of a second allogeneic transplant in patients who experienced primary or secondary graft rejection. The enhanced therapeutic efficacy of this reduced-intensity regimen that allowed consistent donor-derived hematopoietic engraftment after initial allo-graft rejection warrants further study. Disclosures Langston: Astellas Pharma: Other: Research Support; Incyte: Other: Research Support; Jazz Pharmaceuticals: Other: Research Support; Chimerix: Other: Research Support; Takeda: Other: Research Support; Kadmon Corporation: Other: Research Support; Novartis: Other: Research Support; Bristol Myers Squibb: Other: Research Support. Waller:Pharmacyclics: Other: Travel expenses, Research Funding; Cerus Corporation: Other: Stock, Patents & Royalties; Chimerix: Other: Stock; Cambium Oncology: Patents & Royalties: Patents, royalties or other intellectual property ; Amgen: Consultancy; Kalytera: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: the use of pentostatin as part of a conditioning regimen

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Successful Re-Engraftment after Second Allogeneic Transplantation for Graft Failure in Patients with Refractory Hematologic Malignancies.

Blood ◽

10.1182/blood.v104.11.5120.5120 ◽

2004 ◽

Vol 104 (11) ◽

pp. 5120-5120

Author(s):

Don A. Gabriel ◽

James Coghill ◽

Thomas C. Shea ◽

Terrance Comeau ◽

Robert Irons ◽

...

Keyword(s):

Stem Cell ◽

T Cell ◽

None None ◽

Graft Failure ◽

Fatty Infiltration ◽

Conditioning Regimen ◽

Chronic Phase ◽

Myelogenous Leukemia ◽

Unrelated Donor ◽

Grade Ii

Abstract Graft failure (GF), either primary or after transient engraftment, following matched, related allogeneic hematopoetic stem cell transplantation (HSCT) without T-cell depletion is usually less than 3% for hematological diseases. Graft failure using non-T-cell depleted unrelated donors in chronic myelogenous leukemia (CML) as reported by the national marrow registry is approximately 9.7%. For aplastic anemia, the incidence of graft failure is estimated to be 10%. In this report, we present 3 patients (Pts) with GF following unrelated ablative allogeneic HSCT (two with peripheral blood stem cells and one with bone marrow). Pt. 1 had transient engraftment and Pts 2 & 3 had primary GF. Their relevant demographics are as follows: TABLE 1 Disease Unrelated Donor Age/Sex GVHD: BMT1 GVHD: BMT2 PTLD Pt1 CML, 1st Chronic Phase Matched 29/F None Grade II Yes Pt2 MDS Matched 57/M None None No Pt3 MDS/AML 1ag Mismatched 55/M None None No All patients were initially conditioned with alemtuzumab (A) 30mg/day on days −8 to −6, fludarabine (F) 30mg/m2/day on days −7 to −3, and busulfan .8mg/kg x 16 doses (two patients) or x 8 doses (one patient) on days −5 to −2. Conditioning for HSCT #2 included cyclophosphamide 50mg/kg/day, Mesna 50mg/kg/day, and thymoglobulin 2.5mg/kg/day on days −5 to −2. Graft versus host disease (GVHD) prophylaxis included tacrolimus for both HSCT transplants, and low dose methotrexate (3 doses) combined with prednisone (2mg/kg) on days 0–18 followed by a two week taper for HSCT #2. The stem cell product and engraftment kinetics are shown below. Significant toxicities after HSCT#2 have included successful resolution of PTLD in patient #1 (who also experienced infection with pulmonary respiratory syncitial virus, BK viruria, and fatty infiltration of the liver). BK viruria was noted in patient #2, as well as hypertension and a modest pericardial effusion with global hypokinesis (but with a normal ejection fraction). Hepatomegaly was documented, but no vaso-occlusive disease was established. Patient #3 developed a cardiac arrhythmia, hypertension, and BK viruria and remains Plt transfusion dependent. Patient #1 had grade II GVHD of the skin and gut, but patients 2 and 3 had none. GVHD has been <grade II. GF occurred in 3/17 Pts with MUD transplants that included alemtuzamab in the conditioning regimen. While GF is unacceptably high, it is encouraging that all 3 Pts. successfully completed 2nd MUD transplant with transfusion and cytokine independence using same donor preceded in Pts. 1 & 2 by depletion of anti-ABO incompatible antibodies in the recipient.[table2]

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