High-Dose Methotrexate (MTX) as Part of a Novel Immunosuppressive Regimen in Canine MHC-Haploidentical Hematopoietic Cell Transplantation (HCT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3180-3180
Author(s):  
Monica S. Thakar ◽  
Ted A. Gooley ◽  
Erlinda B. Santos ◽  
Rainer F. Storb ◽  
Brenda M. Sandmaier
Keyword(s):  
Graft Rejection ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
Canine Model ◽  
Mixed Lymphocyte Culture ◽  
Lymphocyte Culture ◽  
High Dose ◽  
Donor Chimerism ◽  
Early Results ◽  
Novel Strategy

Abstract In a preclinical canine model using major histocompatibility (MHC)-haploidentical littermate peripheral blood stem cell (PBSC) grafts, initial donor chimerism could be achieved after a nonmyeloablative conditioning regimen consisting of monoclonal antibody S5 (anti-CD44) from days −7 to −2, 200 cGy TBI on day 0, and MMF and cyclosporine for postgrafting immunosuppression. However, sustainable donor chimerisms could not be achieved in many of these dogs, with 25 of 44 (57%) rejecting their grafts at a median of 7 weeks after transplant. In order to improve the engraftment rate, a novel strategy to overcome the immunological barrier created by this MHC-haploidentical setting was developed. By adding single, progressively higher doses of MTX on day+3 after transplantation to the above regimen, we hoped to control host T and NK cells, both of which contribute to graft rejection in MHC-haploidentical HCT, and to target alloreactive donor T cells which are responsible for graft-versus-host disease (GVHD). Once dose toxicity is established, this system will also allow the study of transplants using gene-modified, MTX-resistant CD34 selected PBSC, which can provide additional intrinsic graft protection on exposure to MTX. To date, 11 dogs have been transplanted using the above regimen and adding either 50 (n=5), 100 (n=3), or 200 (n=3) mg/m2 MTX on day +3 followed by leucovorin rescue on days +4 and +5. Early results showed that 4 of 5 dogs experienced graft rejection in the MTX50 group, 0 of 3 dogs rejected in MTX100 (p=0.047, Monte Carlo), and all 3 dogs in MTX200 have continued to exhibit stable mixed chimerisms from +42 to +76 days after transplant. Dogs in all 3 cohorts had rapid engraftment within 1 week, with similar average peak mononuclear cell (MNC) chimerisms at comparable timepoints (83% at 5 wks, 88% at 6 wks, and 80% at 5 wks at MTX50, 100, and 200 respectively). None of the 11 dogs have shown evidence of GVHD or MTX toxicity, and all dogs cleared MTX within 48 hours. All dogs exhibited early donor tolerance on mixed lymphocyte culture assays within 2 weeks and preserved NK activity posttransplant. While these data are preliminary, adding single, progressively larger doses of MTX on day +3 to a novel, nonmyeloablative conditioning regimen appeared to improve engraftment among MHC-haploidentical canine recipients with no signs of GVHD. There was high initial donor chimerism without undue early toxicity. Further, this study will aid in our establishment of high-dose, posttransplant MTX as a way of promoting sustained donor chimerism after transplanting CD34 selected, MTX-resistant canine PBSC in the MHC-haploidentical setting. This preclinical data serve as a basis for developing nonmyeloablative transplant options for patients without HLA-identical donors.

Conversion of Low Donor Chimerism Following Nonmyeloablative Conditioning for Hematopoietic Cell Transplantation (HCT) Using Pentostatin and Donor Lymphocyte Infusion (DLI).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 186-186 ◽  
Author(s):  
Brenda M. Sandmaier ◽  
David G. Maloney ◽  
Michael B. Maris ◽  
Thomas R. Chauncey ◽  
Michael Pulsipher ◽  
...  
Keyword(s):  
At Risk ◽  
Graft Rejection ◽  
Hematopoietic Cell Transplantation ◽  
Median Number ◽  
Infectious Complications ◽  
Donor Lymphocyte Infusion ◽  
Immunosuppressive Drug ◽  
Unrelated Donor ◽  
Donor Chimerism ◽  
Patients At Risk

Abstract Nonmyeloablative allogeneic HCT from both related or unrelated HLA-matched donors after pretransplant conditioning with 2 Gy TBI with or without fludarabine and with posttransplantation CSP/MMF has resulted in initial mixed donor/host chimerism in the majority of recipients. While the risk of rejection of HLA-matched related or unrelated donor grafts was <5% with the regimen, low donor CD3 chimerism appeared to predict rejection. We previously analyzed the outcomes in patients given DLI for either persistent/recurrent disease or low donor chimerism (Blood. 2004; 103:790). Among patients given DLI for low or falling donor CD3 chimerism, success was seen only with pre-DLI CD3 chimerism levels >40%. Among patients receiving DLI for disease, those with disease responses had chimerism levels >90% after DLI, supporting the concept that full chimerism was necessary to eradicate malignant cells and exert graft-vs-tumor effects. Therefore, a protocol was developed to evaluate safety and efficacy of the immunosuppressive drug pentostatin given before DLI to reverse pending graft rejection. Patients considered at risk for rejection had low (<50%) or declining (>20%) donor CD3 chimerism and persistent or stable (including CR) malignant disease; they had no ongoing acute grades II-IV GVHD nor chronic extensive GVHD. Eight patients have been treated a median of 100 (range 54–339) days after HCT. They were originally conditioned for HCT with 2 Gy TBI with (n=7) or without (n=1) fludarabine (30 mg/m2 per day x 3 days) and given both donor and host immunosuppression with MMF and CSP after HCT. Donors were HLA-matched related (n=6) or unrelated (n=2). Diagnoses included NHL (n=2), CLL (n=2), AML (n=1), CML (n=1), and multiple myeloma (n=1); median patient age was 54.5 (range 44–66) years. The patients received pentostatin (4 mg/m2) 2 days before DLI (107 CD3 cells/kg); no post-DLI immunosuppression was given. The median donor CD3 chimerism level before pentostatin and DLI was 29.5 (range 5–34)%. Five patients developed neutropenia and the median number of days of ANC <500 was 11 (0–36) days. Four of 8 patients showed increases of donor CD3 chimerism levels ranging from 63–100%. All 4 patients developed acute GVHD (Grades II n=2; III n=2), and two, chronic extensive GVHD. Currently all 4 patients are alive (CR=3; PR=1) a median of 218 (66–293) days after DLI and 305 (127–377) days after HCT. In the remaining 4 patients, donor CD3 chimerism remained at 5–25% following DLI; two patients received second HCT from the original donors for persistent low chimerism and aplasia, one patient died in CR from infectious complications, and the second is alive in CR with persistent low donor chimerism day 141 following the second HCT. The remaining two patients with low donor chimerism are alive in relapse 157 and 395 days after DLI and 255 and 734 days, respectively, after HCT. In summary, preliminary findings suggest that immunosuppression with pentostatin followed by DLI may be more effective for conversion to full donor chimerism then DLI alone for patients at risk for graft rejection after a nonmyeloablative HCT.

Phase I Study of Bortezomib, (BTZ) Followed by High-Dose Melphalan, (HD Mel) and BTZ as Conditioning Regimen for Tandem Peripheral Blood Stem Cell Transplants (TanPSCT) in Patients with Primary Refractory Multiple Myeloma (MM) and Plasma Cell Leukemia (PCL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5131-5131 ◽  
Author(s):  
Todd Alekshun ◽  
Christine Mcisaac-Simonelli ◽  
Mohamed Kharfan-Dabaja ◽  
William Dalton ◽  
Benjamin Djulbegovic ◽  
...  
Keyword(s):  
Median Time ◽  
Risk Group ◽  
Single Agent ◽  
Conditioning Regimen ◽  
High Dose ◽  
Fish Analysis ◽  
Newly Diagnosed ◽  
Poor Risk ◽  
Early Results ◽  
Pathway Gene

Abstract Background: Approximately 25% of patients with newly diagnosed (MM) fail to respond and progress while receiving conventional induction. As a result, these patients have primary refractory disease. Even though these patients still benefit from HD chemotherapy, their PFS ranges from 4–8 months, while OS is approximately 12 months. PCL accounts for approx. 2% of newly diagnosed MM patients and represents the most aggressive form of disase. These patients often do not respond to standard systemic cytotoxic therapies and their median survival is less than 12 months. Therefore, novel treatment approaches are paramount for patients with primary refractory MM and PCL. The proteasome inhibitor BTZ has been shown to sensitize myeloma cells to melphalan both in vitro and in vivo, but the mechanism is not well understood. In this study we examine the effects of BTZ, followed by BTZ and HDMel as conditioning regimen for TanPSCT in this poor-risk group. Methods: Patients with primary refractory MM or PCL received 2 cycles of BTZ at 1.3 mg/m2. followed by HD Mel (200 mg/m2) and one dose of BTZ at 0.7 mg/m2, 1.0 mg/m2 or 1.3 mg/m2, as a conditioning regimen prior to TanPSCT. The dose of BTZ was given immediately after the last dose of HD Mel. Bone marrow(BM) samples were collected at baseline, on day 4 and after 2 cycles of BTZ, and at 3 months after TanPSCT, for GEP and Fanconi anemia(FA) pathway genes assessment. Results: To date, 17 patients have been enrolled and treated, and 11 patients are evaluable for response. Median age is 59 years (46–70) with the following myeloma distribution: 55% IgA and 45% IgG. FISH analysis showed the following: del 13q (44%), t (4; 14) (11%), t (11; 14) (11%), trisomy 11 (11%), and polyploid (11%); standard karyotype was normal in 88% of patients and complex karyotype in 12%. Median time to WBC engraftment (days) was 13 and 12 after the first and second transplant, respectively. Median time to plt engraftment (days) was 20 and 17, after the first and second transplant, respectively. There were no dose limiting toxicities. Observed grade 3 toxicities were related to the conditioning regimen and similar to those observed with HDMel alone. One patient developed diffuse alveolar hemorrhage after the first cycle of BTZ, which resolved, but was removed from study. After 2 cycles of BTZ, 45% of patients achieved PR, and 55% had stable disease. Overall response rate at 3 months from the second transplant increased to 90%(CR=36%,VGPR=27% andPR=27%). Only 1 patient developed progressive disease after the first transplant. Evaluations of BM samples by GEP and FA pathway gene expression are underway. Conclusions: Single agent BTZ induced responses in 45% and the combination of HD Mel and BTZ as conditioning regimen for TanPSCT was well tolerated and improved response rates to 90%. These early results suggest that this regimen is very active in this poor-risk group. Evaluation of collected BM samples for GEP and FA pathway genes may provide important insight into the mechanisms associated with the observed synergy between BTZ and HD Mel. A Phase II study is underway.

Allogeneic Hematopoietic Cell Transplantation (allo-HCT) Can Induce Durable Remission in Heavily Pretreated Relapsed Hodgkin Lymphoma. (HL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1192-1192
Author(s):  
Robert Chen ◽  
Joycelynne Palmer ◽  
Leslie Popplewell ◽  
Jessica Shen ◽  
Eileen Smith ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
High Dose ◽  
Unrelated Donor ◽  
Heavily Pretreated

Abstract Abstract 1192 Poster Board I-214 Background: Even though Hodgkin lymphoma (HL) is a curable disease, about, 20-30% patients are either refractory to induction chemotherapy or relapse post treatment. High dose chemotherapy and autologous HCT has been shown to be an effective salvage therapy for patients with relapsed HL. However, relapse continues to occur after auto-HCT, especially in patients with chemoresistant or poor-risk features at relapse. The prognosis of these patients is poor with limited options of treatment. Although allo-HCT offers both cytoreduction and potential graft-versus-tumor effect, its use in relapsed HL has been limited by non-relapse mortality (NRM) and patient co-morbidities induced by numerous prior treatments. To examine the potential impact of allo-HCT on survival and disease outcomes, we performed retrospective analysis of allo-HCT in relapsed/refractory HL to determine if allo-HCT can induce long-term remission in heavily pretreated relapsed HL. Results: Between January 2003 and December 2008, 29 patients with relapsed HL underwent allo-HCT at City of Hope National Medical Center. The median age was 37 (range: 14-63). 20 (69%) patients were chemosensitive at time of allo-HCT. 17 (59%) patients had prior auto-HCT. 16 (55%) patients received matched siblings and 13 (45%) received unrelated donor cells. 20 (69%) patients had prior radiation treatments. The median number of prior regimens was 5 (range: 2-8). 23 (79%) patients underwent a non-myeloablative conditioning regimen while 6 (21%) patients had a myeloablative regimen. 14 (48%) patients received Tacrolimus/Sirolimus as graft versus host disease prophylaxis and 15 (52%) patients received a combination of Cellcept/CsA, Cellcept/CsA/MTX, Tacrolimus/MTX, or Tacrolimus/Sirolimus/MTX. With a median follow up of 31.9 months (range: 9.7-69.1) for surviving patients, the results show: Conclusion: Allogeneic hematopoietic cell transplantation in heavily pretreated relapsed Hodgkin's lymphoma is feasible, tolerable, and can induce durable clinical remissions. Disclosures: No relevant conflicts of interest to declare.

A Phase II Trial Combining Radiolabeled Anti-CD45 Antibody with Fludarabine and Low-Dose Total Body Irradiation (TBI) Followed by Related or Unrelated Hematopoietic Cell Transplantation for Patients Under Age 50 with Advanced Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1924-1924
Author(s):  
Raya Mawad ◽  
Ted A. Gooley ◽  
Joseph G Rajendran ◽  
Darrell R. Fisher ◽  
Ajay K. Gopal ◽  
...  
Keyword(s):  
High Risk ◽  
Complete Remission ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
High Dose ◽  
Reduced Intensity Conditioning ◽  
Younger Patients ◽  
Reduced Intensity Conditioning Regimen ◽  
Total Body ◽  
Reduced Intensity

Abstract Abstract 1924 Innovative therapeutic approaches are needed to reduce the morbidity and high relapse rates in patients with advanced AML or high-risk MDS following myeloablative hematopoietic cell transplantation (HCT). Success with stable donor chimerism and low toxicity following infusion of allogeneic peripheral blood stem cells (PBSC) with reduced-intensity regimens affords an opportunity to induce a graft-versus-leukemia (GVL) effect with minimal acute morbidity. GVL effects, however, appear to be most potent in patients with low tumor burden at the time of HCT. In an attempt to improve outcomes, we previously transplanted 58 patients older than age 50 with advanced AML (beyond first remission) or high-risk MDS (≥5% marrow blasts at the time of HCT) in a Phase I trial using 131I-labeled anti-CD45 antibody (BC8) in conjunction with fludarabine (FLU) and 2Gy total-body irradiation (TBI). Data from this study suggested that 131I-anti-CD45-targeted radiotherapy could be safely integrated into a reduced-intensity conditioning regimen for older, high-risk patients with AML or MDS yielding encouraging survival outcomes. These results prompted us to evaluate a similar strategy in younger patients (ages 16–50) with advanced AML or high-risk MDS who may not be able to receive a high dose HCT conditioning regimen. In this phase I dose–escalation trial 14 patients received a dose of 131I-BC8 that delivered 10–27 Gy of targeted radiation to the healthy organ receiving the highest dose combined with FLU (30 mg/m2 daily for 3 days), 2 Gy TBI, and HLA-matched related (n = 7) or unrelated (n = 7) PBSC grafts. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mycophenolate mofetil. The 131I radiation dose was escalated until the maximum planned dose of 28 Gy was reached without any appreciable dose limiting toxicity. The median patient age was 39.5 (range, 23.8–49.7) years. Thirteen patients had AML, with 9 patients in second complete remission, 3 with primary refractory disease, and 1 in active relapse. One patient had advanced CMML with >5% blasts. Treatment with the 131I-BC8 Ab/FLU/TBI regimen produced a complete remission in 7 patients (50%), and 11 of the 12 evaluable patients had 100% donor CD3+ and CD33+cell engraftment by day 28 after HCT; an additional patient had 79% CD3 and 82% CD33 positive donor marrow cells at day 28. The absolute neutrophil count surpassed 500/μL at a median of 15 (range, 13–22) days. Self-sustained platelet levels of 20,000/μL were reached at a median of 11 (range, 11–27) days after HCT. Five patients (36%) are surviving relapse-free 46 to 99 months (median 87 months) after HCT. Seven patients (50%) have died, with five patients relapsing 0.9 to 45 months after HCT. No non-relapse mortality occured by day 100; however, two patients died 14 and 18 months after HCT of cardiomyopathy and GVHD complications, respectively. This study demonstrates that, in addition to a standard reduced intensity conditioning regimen, an average of 27 Gy of targeted 131I radiotherapy can be delivered to bone marrow, an average of 20Gy to the liver, and an average of 84 Gy to the spleen without a marked increase in day 100 mortality for younger patients. This strategy may thus provide a reasonable alternative for patients with high-risk AML/MDS who may not be able to tolerate a high dose conditioning HCT. Disclosures: No relevant conflicts of interest to declare.

Long-term outcomes of survivors of autologous hematopoietic-cell transplantation for refractory and relapsed Hodgkin’s Disease

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6554-6554
Author(s):  
K. A. Goodman ◽  
V. Serrano ◽  
E. R. Riedel ◽  
S. Gulati ◽  
C. H. Moskowitz ◽  
...  
Keyword(s):  
Hematopoietic Cell Transplantation ◽  
Univariate Analysis ◽  
Conditioning Regimen ◽  
Hematopoietic Cell ◽  
High Dose ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Risk Of Death ◽  
Increased Risk

6554 Background: With improvements in survival among refractory/relapsed Hodgkin’s Lymphoma (HL) patients after high-dose chemo-radiotherapy and autologous hematopoietic-cell transplant (AHCT), it is important to evaluate risk of late complications in this heavily treated population. Methods: From 1985–1998, 218 refractory/relapsed HL patients were treated on high dose chemo-radiotherapy and AHCT salvage protocols. 153 (70%) surviving ≥2 years after AHCT were analyzed. All received either radiotherapy with initial therapy or total lymphoid irradiation and involved field boost with the conditioning regimen (43%). Information from surviving patients was obtained through a self-administered questionnaire. The NDI was queried to determine vital status and cause of death. Primary endpoint was non-HL mortality, defined as mortality due to cardiac causes, infection or second malignancy (SM). Competing risk methods were used to calculate cause-specific mortality rates and examine its predictors. All events were calculated from 2 years post-AHCT to date of death/last follow-up. Results: Median follow-up time was 11 years. There have been 51 deaths, 32 due to HL and 19 due to other causes. Eleven deaths were due to SM: AML (3), MDS (2), NHL (2), NSCLC (2), gastric and colon cancer. There were 8 non-SM deaths: cardiac toxicity (4), infection, aplastic anemia, suicide, unknown causes (1 each). The 10 and 15-year overall survival (OS) rates are 64% and 57%, respectively. The 10-year cumulative incidence of death from HL and from non-HL causes were 22% and 13.5% ( table ). By univariate analysis, increased risk of death due to SM was associated only with higher age at AHCT (p=0.02). Conclusions: While HL initially accounts for the majority of deaths among patients surviving high-dose therapy, the HL mortality rate plateaus and risk of death from non-HL mortality increases after 5 years. Yet, even at 15-years, SM risk does not exceed that observed in patients treated with standard regimens. [Table: see text] No significant financial relationships to disclose.

Low-Dose Total Body Irradiation (TBI) and Fludarabine Conditioning for Hematopoietic Cell Transplantation (HCT) in Patients with HLA-Class I Mismatched Donors.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3067-3067
Author(s):  
Hirohisa Nakamae ◽  
Barry Storer ◽  
Thomas Chauncey ◽  
Michael Pulsipher ◽  
Finn Petersen ◽  
...  
Keyword(s):  
Graft Rejection ◽  
Low Dose ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Early Death ◽  
Hla Class I ◽  
Disease Status ◽  
Class I ◽  
Myeloablative Conditioning

Abstract Use of HLA-mismatched unrelated donors after myeloablative conditioning is an effective treatment of blood disorders when HLA-matched donors are not available. However, the feasibility of HLA-mismatched HCT following nonmyeloablative conditioning is not well established. We previously demonstrated in over 1200 patients (pts) that a nonmyeloablative conditioning regimen consisting of 2 Gy TBI and fludarabine (90 mg/m2) followed by post-grafting immunosuppression with MMF/CSP was an effective approach for HCT from 10/10 HLA-matched donors. Here we report the results of a clinical trial aimed at determining whether stable hematopoietic grafts from HLA-class I mismatched donors could be safely established after nonmyeloablative conditioning. Pts were conditioned with fludarabine and 2 Gy TBI, followed by extended immunosuppression with CSP (day −3 to +180; tapered by +365) and MMF (tid days 0 to +100; tapered by +150). 46 pts ineligible for myeloablative conditioning were enrolled on this multi-institutional study through April/07. 36 unrelated and 3 related donor-recipient pairs were mismatched in both the HVG and GVH vectors. 43 unrelated pairs were mismatched for at least one antigen (AG) (15 at HLA-A, 5 at HLA-B, 22 at HLA-C) except one pt who had two allele mismatches (HLA-A and B). All 3 related pairs were mismatched for one HLA-A AG. 13 pts, in addition to the AG mismatch, had an allelic mismatch (3 at HLA-A, 4 at HLA-B, 6 at HLA-C). All pts were matched for HLA-DRB1 and HLA-DQB1 at the allele level. Diagnoses included NHL (n=17), HD (n=5), AML (n=11), ALL (n=5), CLL (n=3), MM (n=4) and MDS/AML (n=1). The median age of pts was 56 (range 13–69) years and median time from diagnosis to HCT was 32 (range 5–205) months. Disease status at time of HCT included CR (n=23), PR (n=11), stable disease (n=2), and refractory relapse (n=10). Before HCT, pts had received a median of 7 (range 2–15) courses of therapy. 43% had failed myeloablative HCT (autologous n=18; allogeneic n=2). All pts received G-CSF mobilized PBSC containing median doses of 7.3 ×106 CD34 and 2.4 × 108 CD3 cells /kg. 12 pts were not evaluable for the graft rejection outcome (3 early death, 7 mismatched in GVH vector only, 2 tandem auto-allo). The remaining pts showed median percentages of donor peripheral blood T cell, granulocyte and marrow chimerism of 100% at all time points (on days 28, 56, and 84). Two pts experienced graft rejection but had a successful 2nd HCT from the same or an alternative donor. 35 of the 46 pts developed acute GVHD (2 grade I, 21 grade II, 5 grade III, 7 grade IV) and 15 developed chronic GVHD. At 2 years, the cumulative probabilities of relapse/progression and non-relapse mortality were 30% and 45%, respectively. The 2 year Kaplan-Meier estimates of OS and PFS were 27% and 25%. This study demonstrates that nonmyeloablative conditioning using fludarabine and low-dose TBI can be successfully used for grafts from pts with HLA- class I mismatched donors.

Donor Specific Tolerance Of Renal Allografts Following Haploidentical In Utero Hematopoietic Cell Transplantation In The Canine Model

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2007-2007
Author(s):  
Erik G. Pearson ◽  
Jesse D Vrecenak ◽  
Tricia R Bhatti ◽  
William H. Peranteau ◽  
Alan W. Flake
Keyword(s):  
Renal Transplantation ◽  
Organ Transplantation ◽  
Cell Transplantation ◽  
Murine Model ◽  
Hematopoietic Cell Transplantation ◽  
Canine Model ◽  
Positive Control ◽  
Donor Chimerism ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

Abstract Introduction In utero hematopoietic cell transplantation (IUHCT) can result in allogeneic mixed hematopoietic chimerism and associated donor specific tolerance (DST). We have reported a 1-2% donor chimerism threshold for consistent DST in the murine model as defined by the ability to enhance engraftment postnatally with a same donor minimal conditioning BMT, and have confirmed this finding in the canine model of IUHCT. Recently, we have optimized the canine model and achieved higher levels of chimerism (average>10%). As prenatal tolerance induction for postnatal organ transplantation is one of the clinical goals of IUHCT, we hypothesized that the presence of donor chimerism (>2.0%) after haploidentical IUHCT in the canine model would be sufficient to allow same donor renal transplants without immunosuppression. Method Stable mixed hematopoietic macrochimerism was documented by VNTR after haploidentical IUHCT performed at 40 days gestation using maternal donor BM cells in 4 pups (chimerism levels 3-38%). One positive control canine with no detectable chimerism following IUHCT also underwent haploidentical renal transplantation. Renal transplantation was performed from the maternal donor at ages between 12 and 18 months, and the pups were serially followed by ultrasound of the graft, blood chemistry and urinalysis post transplant. At 60 days an open biopsy of the allograft was taken and at 6 months a graft nephrectomy was performed for histologic analysis. Results Following transplantation, all recipients demonstrated blood flow to the renal cortex and all laboratory values were within normal ranges. At 60 days and 6 months 3 of the 4 recipients demonstrated a graft without evidence of acute or chronic rejection. The recipient with the lowest level of chimerism (3%) demonstrated evidence of mild interstitial nephritis (Banff class 1 rejection) following transplantation at the time of renal biopsy which increased in severity to severe interstitial fibrosis and moderate tubular atrophy (Banff class 3 rejection) at the time of graft nephrectomy. The positive control canine without detectable chimerism demonstrated clinical and histologic evidence of acute rejection within one week of transplantation. Conclusion Our results support the ability of IUHCT to induce DST for haploidentical organ transplantation, in a large animal model, without the need for immunosuppression. In agreement with previous studies in the murine model there appears to be a threshold level of donor chimerism required for associated DST. Although our numbers are not adequate to establish absolute thresholds of chimerism predictive of DST for organ transplantation, it appears to be slightly higher than the 1-2% threshold established for cellular transplantation. Disclosures: No relevant conflicts of interest to declare.

A Phase 2 Study of High-Dose Melphalan Plus Bortezomib (Mel/Vel) Conditioning Followed By Autologous Hematopoietic Cell Transplantation in Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3987-3987
Author(s):  
Taiga Nishihori ◽  
Jose L Ochoa-Bayona ◽  
Rachid Baz ◽  
Kenneth H. Shain ◽  
Christine Simonelli ◽  
...  
Keyword(s):  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
High Dose ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Autologous Hct ◽  
High Dose Melphalan ◽  
Autologous Hematopoietic Cell Transplantation

Abstract Background: High-dose melphalan followed by autologous hematopoietic cell transplantation (HCT) remains the integral component of multiple myeloma (MM) therapy in the era of novel agents. We published our prior study with the use of high-dose melphalan + bortezomib (Mel/Vel) conditioning regimen for tandem transplants in refractory MM patients (Nishihori, et al. Br J Haematol 2012). We designed a phase 2 trial using MelVel conditioning followed by autologous HCT in patients with newly diagnosed chemosensitive MM (NCT 00948922). Methods: Sixty seven newly diagnosed MM patients who achieved ≥ partial response (PR) to induction therapy with ≤grade 1 peripheral neuropathy (PN) were enrolled from 12/2009 to 06/2014. Patients received high-dose melphalan at 100 mg/m2 IV for 2 days, immediately followed by 1 dose of bortezomib at 1.3 mg/m2 (Mel/Vel conditioning). Maintenance therapy was not prescribed by design. The protocol later was modified to include maintenance bortezomib subcutaneously (started at 3 months after HCT) at 1.3 mg/m2 weekly x4, every 8 weeks, for a total of 6 cycles. Progression-free and overall survival (PFS and OS) estimates were calculated using Kaplan-Meier method. Results: A total of 67 patients received autologous HCT. The median age was 58 (25 - 73) years with the following disease characteristics: Durie-Salmon stage, 3A (72%) and 3B (10%); IgG (55%), IgA (21%), IgD (1%), and light chain (22%). High-risk cytogenetics/FISH were seen in 28% of patients. The median beta-2 microglobulin was 3.3 (range, 1.3 – 34.8). Induction regimens were bortezomib-based in 39%, lenalidomide-based in 19% and, both bortezomib and lenalidomide in 42%. Median time from initiation of induction to HCT was 204 days (range, 101 - 664). Responses prior to HCT were stringent CR (sCR) 21%, CR 12%, very good partial response (VGPR) 34%, and PR 33%. Neutrophil engraftment was achieved after a median of 11 days (range, 10 – 14) and platelet engraftment occurred after a median of 15 days (range, 11 – 22). Median CD34 cell dose was 3.8 x 106/kg (range, 2 – 20.08). Responses at 3 months after HCT (in 64 evaluable patients) were sCR 47%, CR 14%, VGPR 20%, PR 16% and progressive disease 3%. Bortezomib maintenance was prescribed to 31 patients (46%). Prevalence of grade 1 PN before (n=67) and at 3 months (n=64) after HCT were 37% and 38%, respectively. Two patients withdrew consent to initiate maintenance and 1 patient was unable to initiate maintenance due to grade 1 PN (baseline PN of 0). At the time of review, a median number of maintenance delivered was 4 (range, 1-6) and only one patient required dose reduction. The 2-year PFS and OS estimates are 62% (95% CI 0.47 – 0.75) and 90% (95% CI 0.80 – 0.97) with a median follow-up of 21 months (range, 2 – 54). The 1-year PFS estimates were 85% (95% CI 0.65 – 0.97) for bortezomib maintenance vs. 81% (95% CI 0.66 – 0.92) for no maintenance (p=0.6). There were no significant differences in PFS or OS stratified by cytogenetic/FISH risk status. There was no transplant related mortality. Conclusions: The combination of bortezomib and high-dose melphalan (Mel/Vel) as conditioning regimen for autologous HCT is well tolerated and appears to improve responses after HCT. Weekly x4 post HCT bortezomib maintenance given every 8 weeks appears to be well tolerated and is a promising strategy for eligible patients. Longer follow up is required to assess the benefit of post HCT maintenance strategy. Disclosures Baz: Millennium: Research Funding. Alsina:Millennium: Consultancy, Research Funding.

Busulfan / Melphalan / Bortezomib (Bu-Mel-Vel) Vs. High Dose Melphalan As Conditioning Regimen For Autologous Hematopoietic Cell Transplantation In Multiple Myeloma (MM)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3357-3357 ◽  
Author(s):  
Tulio E. Rodriguez ◽  
Parameswaran Hari ◽  
Patrick J Stiff ◽  
Xiaobo Zhong ◽  
Danielle Sterrenberg ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Maintenance Therapy ◽  
Cell Transplantation ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
High Dose ◽  
High Dose Melphalan ◽  
Autologous Hematopoietic Cell Transplantation

Abstract Background High dose melphalan (MEL) preceding autologous hematopoietic cell transplantation (HCT) for MM continues to be the standard of care. No regimen has been clearly proven superior to MEL 200 mg/m2 (MEL 200). The combination of Busulfan (Bu) and MEL was shown to improve progression free survival (PFS) (Lahuerta, et al; Haematologica. 2010 Nov; 95 (11):1913-20). The combination of bortezomib (Vel) with MEL also demonstrated superior PFS vs. MEL alone using historical controls (Roussel et al; Blood. 2010; 115:32-7). We studied a conditioning regimen combining Bu, MEL and Vel (BuMelVel) in an open label phase II study aimed at improving PFS after HCT for MM. To assess the potential value of this novel regimen, we performed a comparative analysis between BuMelVel and a cohort of patients conditioned with MEL 200 from the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Methods Between July 2009 and May 2012, 43 eligible patients received BuMelVel conditioning followed by HCT. Bu was administered daily intravenous (IV) for a total of 4 days with the first 2 days (day -6, -5) at fixed dose of 130 mg/m2 over 3 hours and the subsequent 2 doses (day -4, -3) adjusted to achieve a target area under the concentration-time curve (AUC) total of 20,000 mM* min by performing pharmacokinetic (PK) analysis after the first dose of IV Bu. Mel 140 mg/m2 and Vel 1.6 mg/m2 were administered IV on Day-2 and Day -1 respectively. Outcomes were compared with a contemporaneous North American cohort (n=162) receiving single agent MEL 200 conditioning from the CIBMTR database. Controls were matched on age, sex, Karnofsky performance status (KPS), stage and interval from diagnosis to HCT. Multivariate analysis of Relapse, PFS, and overall survival (OS) was performed. Median follow up of survivors was 25 months. Planned maintenance therapy was not used. Results Age, gender, KPS, isotype, and stage were similar between groups (Table 1.). The MEL 200 cohort had more standard risk patients per Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) (78% vs. 40% in BuMelVel, p <0.0001) and more patients with only 1 prior line of therapy pre-HCT (67% vs. 47%, p = 0.02). Platelet and neutrophil engraftment kinetics were similar. Veno-occlusive disease (VOD) was not observed in the BuMelVel group and there was no non-relapse mortality (NRM). The incidence of relapse and PFS at 1 year were superior in the BuMelVel cohort (Table 1.). OS was similar between the cohorts. In multivariate analysis, PFS was superior in the BuMelVel cohort (HR for relapse/death in MEL 200 =1.87, p=0.04). Lack of a very good partial response or higher (≥VGPR) prior to HCT was associated with inferior PFS whereas lower KPS (<80) and higher international stage were associated with mortality. Conclusion PK directed dosing of Bu can be safely combined with Mel 140 followed by bortezomib without higher risk of VOD or NRM and in the absence of maintenance therapy. Within the constraints of a short follow up and uncontrolled post-transplant salvage therapies on both groups, no difference in OS has yet been observed. This novel conditioning regimen is safe and was associated with superior PFS compared with similarly matched controls and warrants further testing. Disclosures: Rodriguez: Otsuka: Research Funding; Millennium: Research Funding, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Vesole:Millennium: Speakers Bureau.

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