Fludarabine, Cytarabine, Busulphan, and Cyclophosphamide (FABC) as Conditioning Regimen in Hematopoietic Stem Cell Transplantation for Treatment of 92 Patients with Hematologic Malignancies.

Abstract Abstract 1147 Poster Board I-169 In the past twenty years, allogeneic hematopoietic stem cells transplantation (Allo-HSCT) has been accepted as the most effective treatment for many hematologic malignancies. However, the successful rate of allo-HSCT has been limited by transplantation-related mortality and malignancies relapse, no matter using traditional intensity conditioning or reduced-intensity conditioning. In this study, we presented ninety-two patients with hematopoietic malignancies received fludarabine combinasion with modified Bu/Cy (FABC) conditioning regimen before allogeneic hematopoietic stem cell transplantation. Ninety-two patients with hematological malignancies (58 males, 34 females) ranged in age from 14 to 50 (median 28) years. These patients were diagnosed with acute lymphoblastic leukemia (ALL, n=30), acute myelogenous leukemia(AML, n=24), chronic myelogenous leukemia (CML, n=33; CP, n=27; CML-AP, n=5; CML-BC, n=1), myelodysplastic syndrome ( MDS, n=3), chronic myelomonocytic leukemia (CMML, n=1), and one patient coexisted chronic myelomonocytic leukemia and T lymphoblast cell lymphoma. Fifty-five (59.8%) patients were at high risk. From June 2004 to October 2008, 92 patients gave their informed consent and received conditioning regimen with fludarabine-based modified Bu/Cy (FABC conditioning regimen) in allo-HSCT. The FABC regimen consist of cytarabine 2.0 g/ m2 on day -9, busulphan (Bu) 3.2 mg/kg per day for intravenous on days -8 to day-6, followed by cyclophosphamide (Cy) 60 mg/kg per day on days -5 and day-4, combined fludarabin 30 mg/m2 per day for three consecutive days, on days -6 to day-4, and Me-CCNU (1-(2-Chloroethyl)-3-(4-ethylnitrobiphenyl Cylohexyl4)-1- Nitrosourea) 250 mg/m2 on day -3. Graft-versus-host-disease(GVHD) prophylaxis consisted of cyclosporine A, short-term MTX and Mycophenolate Mofefil (MMF 1.0g/day, on d-8 to d-1). Anti-T-lymphocyte globulin (2.5 mg·kg-1·d -1, on d-3 to d-1) was added to patients with mismatched sibling or unrelated donors. Follow-up was performed on 30 December, 2008. Ninety-two patients engrafted successfully, the median time for ANC >0.5×109/L was 12 (8 to 22) days, and for BPC > 20×109/L was 12 (7 -32) days. Detected by short tandem repeat (STR)-PCR, complete donor chimerism was comfirmed in all patients on day +21 or day+30. The incidence of acute GVHD was 25% (23/92), and grades 3 to 4 acute GVHD developed in 8 (8.7%) of 92 patients with in 100 days after HSCT. Chronic GVHD developed in 40(47.6%) of 84 patients who were alive more than 100 days after HSCT, and the incidence of extensive cGVHD was 35.7%(30/84). The transplant related mortality (TRM) was 19.6% (18/92), mainly from severe infection (n=7), acute or chronic GVHD (n=5), transplant associated-microangiopathy (n=2), diffusion alveolar hemorrhage (n=2), and post-transplant lymphoproliferative disorders (n=2). With a median follow-up of 16.2(1.5 to 54.5) months, 70 (76.1%) of the 92 patients were alive and 67(72.8%) were disease-free. The probabilities of OS at 1 year and 2 years was 80% and 72.5%, and DFS was 79.1% and 71.4%, respectively. These results suggest that the fludarabine-based modified Bu/Cy conditioning regimen (FABC) should reduce severe acute GVHD and accelerate hematopoietis resconsition without increasing chronic GVHD and lower leukemia relapse rates even in high-risk patients. Footnotes Corresponding author Disclosure No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood.v108.11.605.605 ◽

2006 ◽

Vol 108 (11) ◽

pp. 605-605

Author(s):

Karen K. Ballen ◽

Corey Cutler ◽

Thomas R. Spitzer ◽

Beow Yeap ◽

Steve McAfee ◽

...

Keyword(s):

Cord Blood ◽

Total Dose ◽

Aplastic Anemia ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Cord Blood Unit ◽

Reduced Intensity ◽

Related Mortality

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

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Similar Incidence of Severe Acute Gvhd and Less Extensive Chronic Gvhd in PBSCT from Unmanipulated Haploidentical Donor Compared with That from Matched Sibling Donor for Patients with Hematologic Malignancies

Blood ◽

10.1182/blood.v126.23.1964.1964 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1964-1964

Author(s):

Honghua Li ◽

Wenrong Huang ◽

Chunji Gao ◽

Liping Dou ◽

Fei Li ◽

...

Keyword(s):

Cohort Study ◽

Stem Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Hematologic Malignancies ◽

Hematopoietic Stem ◽

Sibling Donor ◽

Matched Sibling ◽

Similar Incidence

Abstract Unmanipulated haploidentical hematopoietic stem cell transplantation (haplo-HCT) resulted in encouraging outcomes for treatment of hematologic malignancies and become an alternative option in case of lacking HLA matched sibling donor (MSD). Transplantation with G-CSF mobilized peripheral blood stem cell (PBSCT) has been a stable transplant setting with MSD. Unmanipulated haploidentical donor (haplo-PBSCT) has been applied in patients with hematologic malignancies. However, the characteristics of graft-versus-host disease (GVHD) in unmanipulated haplo-PBSCT are not clear. Here, we report the results of a cohort study on the clinical features of acute and chronic GVHD in haplo-PBSCT compared with PBSCT from MSD in patients with hematologic malignancies. PATIENTS AND METHODS Between July, 2007 and June, 2014, 94 patients with hematologic malignancies received haplo-PBSCT and 100 patients received PBSCT from MSD consecutively at our unit (Table 1). The PBSCs were collected on day 5 and 6 after 4 days of rhG-CSF (5 mg.kg¨C1 °¤day¨C1), then were infused on the day of collection. The conditioning regimen consisted of Bu (9.6 mg.kg-1, iv, days -10~-8), Carmustine, (250 mg.m-2, day -5), cytarabine (8 g.m-2, days -7~-6), CY (120mg kg-1, days -4~-3). Antithymoglobulin (ATG, rabbit; 10 mg.kg-1, days -5~-2) was used for haplo-PBSCT. All recipients received cyclosporine A, mycophenolate mofetil, and short-term methotrexate for GVHD prophylaxis. The endpoint of the last follow-up for all surviving patients was July 15, 2015. RESULTS Among the patients with acute GVHD, there was no difference of the rate of the involved organs between these two groups (skin: 67.4% vs 68.0%, p=1.000; liver: 15.2% vs 20.0%, p=0.742; gut: 33.3% vs 32%, p=1.000). Haplo-PBSCT was associated with higher incidence of acute GVHD grade 2-4 (HR: 3.04, 95% CI: 1.55-5.98, p=0.001) and lower incidence of extensive chronic GVHD (HR: 0.49, 95% CI: 0.24-0.99, p=0.047) compared with MSD PBSCT. There was no difference of the incidence of acute GVHD grade 3-4 between these two groups (haplo-PBSCT, 9.6% vs MSD PBSCT 8.9%, p=1.000). According to NIH criteria, the incidence of severe chronic GVHD was lower in haploidentical group (13.6%) compared with MSD group (40.5%, p=0.041). There was no difference of those for mild and moderate chronic GVHD (mild: 27.3% vs 13.5%, p=0.189; moderate: 59.1% vs 45.9%, p=0.422). CONCLUSION In this cohort study, haplo-PBSCT was associated with similar incidence of severe acute GVHD, lower extensive chronic GVHD and lower severe chronic GVHD compared with MSD-PBSCT. It suggested the potential advantage of ATG in improvement of long-term quality of life of the transplant recipients. Table 1. Characteristics of patients and donors Haploidentical donor, n = 94 Matched sibling donor, n = 100 P value Gender, n (%) Receipt, male 73 (77.7) 64 (64.0) 0.041 Donor, male 63 (67.0) 60 (60.0) 0.371 Age Patient, y, median 27 38 0.055 Donor, y, median 38 39 0.364 Hematologic malignances, n (%) Acute leukemia 72 (76.6) 61 (61.0) MDS 3 (3.2) 21 (21.0) 0.000 CML 5 (5.3) 10 (10.0) Lymphoma 14 (14.9) 8 (8.0) Status of disease, n (%) 0.000 CR1 42 (44.7) 76 (76) CR2 14 (14.9) 5 (5) NR/beyond CR2 38 (40.4) 19 (19) Time to transplant (d) 361 299 0.946 Conditioning Regimen, n (%) 0.354 BuCy 60 (63.8) 66 (66.0) TBIcy 28 (29.8) 23 (23.0) FB 6 (6.4) 11 (11.0) CD34+ in graft (106/kg) 5.86 4.77 0.057 ≥4.60 51 (54.3) 41 (41.0) 0.084 Disclosures No relevant conflicts of interest to declare.

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Single Center Experience of Allogenic Hematopoietic Stem Cell Transplantation in 100 Patients with Myelodysplasia: The Impact of Graft-Versus-Host Disease

Blood ◽

10.1182/blood.v126.23.5537.5537 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5537-5537

Author(s):

Colombe Saillard ◽

Raynier Devillier ◽

Sabine Furst ◽

Jérome Rey ◽

Angela Granata ◽

...

Keyword(s):

Stem Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Hematopoietic Stem ◽

Donor Type ◽

The Impact ◽

Disease Free

Abstract Introduction Allogenic hematopoietic stem cell transplantation (Allo-HSCT) is a curative treatment for patients with myelodysplasia (MDS). However, because of age, MDS patients represent a challenging population for such an intensive treatment. Additionally, the low rate of HLA-identical donor has represented a major limitation in this strategy. Recently, reduced-intensity conditioning (RIC) regimens have made feasible Allo-HSCT in the elderly, although relapse rate might be increased. Additionally, the development of HSCT using alternative donors overcomes HLA-compatibility limitations. Graft-versus-host disease (GVHD) is a major post-transplant event, graft-versus-leukemia effect being counterbalanced by toxicity and impaired quality of life. The aim of this retrospective study was to report outcome of patients with MDS who underwent Allo-HSCT and to study the impact of GVHD. Methods Between 2003 and 2014, 100 consecutive patients presenting with MDS, or MDS-secondary AML, underwent Allo-HSCT in our institution. At diagnosis, 58 patients had ≥ 2 cytopenias. IPPS was low/intermediate-1 in 46% and intermediate-2/high in 54%, R-IPSS was very low/low in 25%, intermediate in 20% and high/very high in 55%. Cytogenetics, according to Disease Risk Index (DRI), was intermediate in 79% and adverse in 21%. Secondary MDS represented 27% of our cohort. Before Allo-HSCT, 42% received 5-Azacytidine, 27% intensive chemotherapy and 9% were transplanted upfront. At the time of Allo-HSCT, the median recipient age was 61 (19-71) years. Median time between diagnosis and Allo-HSCT was 12 months (1-131). After excluding patients transplanted upfront, 31 patients still had ≥5% blasts after treatment. Donors were HLA-matched in 70% (41% related, 29% unrelated), 30% were not HLA-matched (10% unrelated, 7% cord blood, 13% T-repleted haplo-HSCT). Stem cell source was peripheral blood stem cells in 90%. Twelve percent of patients received non-myeloablative (NMA) conditioning regimen, 75% RIC and 13% reduced-toxicity conditioning (RTC) regimens. Post-graft immunosuppression consisted in cyclosporine A (CSA) in 58%, CSA-Mycophenolate Mofetil (MMF) in 15%, CSA-Methotrexate in 14% and CSA-MMF-Cyclophosphamide for haplo-HSCT (13%). Results Median follow-up was 37 months (3-197). The incidence of 3-4 acute GVHD at day 100 was 7% (95% CI = 2-12). The incidence of severe chronic GVHD at 3 years was 19% (95% CI = 11-27). One and 3-year non-relapse mortality (NRM) were 23 and 29% respectively. The cumulative incidence of relapse (CIR) at 1 year and 3 years 24% and 33% respectively. One and 3-year progression-free survival (PFS) were 52% (95% CI = 43-63) and 37% (95% CI = 28-49). One and 3-year overall survival (OS) were 60% (95% CI = 51-71) and 48% (95% CI = 39-60). At one year, 51 patients were alive and disease-free, including 61% (n=31) without immunosuppression. At the end of follow-up, 39 patients were alive and disease-free, including 85% (n=33) without immunosuppression and 77% (n=30) GVHD-free. Time-dependent analysis of GVHD impact (Table 1), adjusted on age, donor-type, DRI and conditioning regimen, revealed that acute GVHD strongly impacts on OS (HR 3.8, 95% IC = 2-7, p<0.01), PFS (HR 3.1, 95% CI = 1.7-5.6, p<0.01) and NRM (HR 12, 95% CI = 5.2-28, p<0.01). Chronic GVHD was statistically significant on CIR (HR 0.16, 95% CI = 0.04-0.7, p=0.02) and NRM (HR 2.8, 95% CI = 1-8, p=0.05). Pre-transplant disease characteristics did not have any impact by univariate analysis. Multivariate analysis did not find any impact of age, donor type, DRI and conditioning regimen in terms of OS, PFS, NRM and CIR. Conclusion Our results suggest that GVHD highly influences outcome, regardless of MDS and Allo-HSCT characteristics. It should be quoted that a significant number of patients are alive, long-term survivors, disease-free and GVHD-free suggesting good quality of life. These results invite defining better strategies of GVHD prevention while retaining disease control magnifying the existing graft-versus-leukemia effect. Table 1. Time-dependent analysis of the impact of acute and chronic GVHD, adjusted on age (< or > 60), donor-type (HLA-matched or not matched), DRI and conditioning regimen (NMA, RIC or RTC). HR 95% CI p Acute GVHD OS PFS NRM CIR 3.8 3.1 12 0.4 2-7 1.7-5.6 5.2-28 0.09-1.7 <0.01 <0.01 <0.01 0.2 Chronic GVHD OS PFS NRM CIR 0.7 0.8 2.8 0.2 0.3-1.5 0.4-1.8 1.01-8 0.04-0.8 0.4 0.6 0.050.02 Disclosures Vey: Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria.

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In vivo CAMPATH-1H prevents graft-versus-host disease following nonmyeloablative stem cell transplantation

Blood ◽

10.1182/blood.v96.7.2419 ◽

2000 ◽

Vol 96 (7) ◽

pp. 2419-2425 ◽

Cited By ~ 407

Author(s):

Panagiotis D. Kottaridis ◽

Donald W. Milligan ◽

Rajesh Chopra ◽

Ronjon K. Chakraverty ◽

Suparno Chakrabarti ◽

...

Keyword(s):

Cyclosporine A ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Hematologic Malignancies ◽

Post Transplantation ◽

Peripheral Blood Stem Cells ◽

Nonmyeloablative Stem Cell Transplantation

Abstract A novel nonmyeloablative conditioning regimen was investigated in 44 patients with hematologic malignancies. The median patient age was 41 years. Many of the patients had high-risk features, including 19 patients with a previous failed transplant. Recipient conditioning consisted of CAMPATH-1H, 20 mg/day on days −8 to −4; fludarabine, 30 mg/m2 on days −7 to −3; and melphalan, 140 mg/m2 on day −2. Thirty-six recipients received unmanipulated granculocyte colony-stimulating factor–mobilized peripheral blood stem cells from HLA-identical siblings, and 8 received unmanipulated marrow from matched unrelated donors. GVHD prophylaxis was with cyclosporine A alone for 38 patients and cyclosporine A plus methotrexate for 6 sibling recipients. Forty-two of the 43 evaluable patients had sustained engraftment. Results of chimerism analysis using microsatellite polymerase chain reaction indicate that 18 of 31 patients studied were full-donor chimeras while the other patients were mixed chimeras in one or more lineages. At a median follow-up of 9 months (range 3 to 29 months), 33 patients remain alive in complete remission or with no evidence of disease progression. Seven patients relapsed or progressed post-transplantation, and 4 of them subsequently died. Four patients died of regimen-related complications. There were no cases of grades III-IV acute GVHD. Only 2 patients developed grade II acute GVHD, and only 1 had chronic GVHD. The estimated probability of nonrelapse mortality was 11%. Although longer follow-up is needed to establish the long-term remission rates, this study demonstrates that this nonmyeloablative preparative regimen is associated with durable engraftment, minimal toxicity, and low incidence of GVHD.

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Influence Of Acute and Chronic Graft-Versus-Host Disease On Outcome After Allogeneic Hematopoietic Stem Cell Transplantation For Chronic Myelomonocytic Leukemia

Blood ◽

10.1182/blood.v122.21.2102.2102 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2102-2102

Author(s):

Hidehiro Itonaga ◽

Masako Iwanaga ◽

Kazunari Aoki ◽

Jun Aoki ◽

Ken Ishiyama ◽

...

Keyword(s):

Cell Transplantation ◽

Acute Gvhd ◽

Proportional Hazards ◽

Chronic Gvhd ◽

Chronic Myelomonocytic Leukemia ◽

Confidential Interval ◽

Hematopoietic Stem ◽

Graft Versus Host ◽

Related Donor ◽

Myelomonocytic Leukemia

Abstract Introduction Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a therapeutic option for chronic myelomonocytic leukemia (CMML), with the possibility that the graft-versus-CMML (GvL) effect has an important role for survival after allo-HSCT. In a clinical situation, GvL effect was assumed to closely correlate with graft-versus-host disease (GVHD). This study aimed to evaluate the influence of acute and chronic GVHD on long-term outcomes for patients with CMML that were treated with allo-HSCT. Patients and Methods Data were obtained from the Transplant Registry Unified Management Program, which includes three data sources of the Japan Society for Hematopoietic Cell Transplantation, the Japan Marrow Donor Program, and the Japan Cord Blood Bank Network. There was a total of 177 records of CMML patients who were 16 years of age or older and had received allo-HSCT between January 1, 1987 and December 31, 2010. Of those, 141 patients had received allo-HSCT without in-vivo or ex-vivo T-cell depletion, and survived with neutrophil engraftment, which were subjects for this analysis. The probability of overall survival (OS) was estimated by Kaplan-Meier method. Disease-associated mortality was estimated with the use of cumulative incidence curves to accommodate the competing events. Semi-landmark plots were used to illustrate the effects of GVHD on OS and cumulative incidence of disease-associated mortality using the median days of the occurrence of GVHD. Univariate and multivariate Cox proportional hazards regression models were used to evaluate variables potentially affecting OS. Fine and Gray proportional hazards models were used to evaluate variables potentially affecting disease-associated mortality. In these hazard models, the occurrence of GVHD was treated as time-varying covariate. Result The median age of recipients was 49 years old. There were 68 transplants from HLA-matched related donor, 10 from HLA-mismatched related donor, 53 from unrelated bone marrow donor, and 10 using unrelated cord blood. One hundred one and 40 patients received myeloabrative and reduced intensity conditioning, respectively. Median survival times after allo-HSCT was 2.8 years. Estimated OS and cumulative disease-associated mortality at 3 years after allo-HSCT were 47.3% (95% confidential interval, 38.5-55.7) and 18.2% (12.2-25.1), respectively. Acute GVHD of grades 1 and 2-4 occurred in 25 and 62 patients, respectively. The median onset of acute GVHD of any grade after allo-HSCT was 22 days (range, 6-80). The analysis using semi-landmark plots revealed that the development of grade 1 acute GVHD was significantly associated with a better OS (p=0.015) and a lower disease-associated mortality (p=0.012) compared with the absence of acute GVHD. However, in multivariate analysis, the emergence of grade 1 acute GVHD was not associated with OS (Hazard ratio (HR) [95% confidential interval], 2.12 [0.69-6.51]; P=0.189) and disease-associated mortality (HR, 1.71 [0.60-4.86]; p=0.31). With a median day of chronic GVHD occurrence after allo-HSCT of 138 (range, 57-669), limited and extensive chronic GVHDs occurred in 17 and 39 patients, respectively. The analysis using semi-landmark plots revealed that the development of limited chronic GVHD related to better OS (p<0.001) and lower disease-associated mortality (p<0.001) compared with the absence and extensive chronic GVHD. In multivariate analysis, OS tended to be better for patients with limited chronic GVHD than the absence of chronic GVHD (HR, 3.86 [0.83-17.9]; P=0.085), while the absence of chronic GVHD possibly affected with the higher disease-associated mortality compared with the emergence of limited chronic GVHD, with a borderline statistical significance (HR, 3.92 [0.91-16.9]; P=0.067). Conclusion Our results showed the efficacy of allo-HSCT for patients with CMML and suggested an important role of GvL linked to chronic GVHD on the better outcome of the patients after receiving allo-HSCT. Disclosures: Fukuda: the Japanese Ministry of Health, Labour, and Welfare: Research Funding.

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In vivo CAMPATH-1H prevents graft-versus-host disease following nonmyeloablative stem cell transplantation

Blood ◽

10.1182/blood.v96.7.2419.h8002419_2419_2425 ◽

2000 ◽

Vol 96 (7) ◽

pp. 2419-2425 ◽

Cited By ~ 4

Author(s):

Panagiotis D. Kottaridis ◽

Donald W. Milligan ◽

Rajesh Chopra ◽

Ronjon K. Chakraverty ◽

Suparno Chakrabarti ◽

...

Keyword(s):

Cyclosporine A ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Hematologic Malignancies ◽

Post Transplantation ◽

Peripheral Blood Stem Cells ◽

Nonmyeloablative Stem Cell Transplantation

A novel nonmyeloablative conditioning regimen was investigated in 44 patients with hematologic malignancies. The median patient age was 41 years. Many of the patients had high-risk features, including 19 patients with a previous failed transplant. Recipient conditioning consisted of CAMPATH-1H, 20 mg/day on days −8 to −4; fludarabine, 30 mg/m2 on days −7 to −3; and melphalan, 140 mg/m2 on day −2. Thirty-six recipients received unmanipulated granculocyte colony-stimulating factor–mobilized peripheral blood stem cells from HLA-identical siblings, and 8 received unmanipulated marrow from matched unrelated donors. GVHD prophylaxis was with cyclosporine A alone for 38 patients and cyclosporine A plus methotrexate for 6 sibling recipients. Forty-two of the 43 evaluable patients had sustained engraftment. Results of chimerism analysis using microsatellite polymerase chain reaction indicate that 18 of 31 patients studied were full-donor chimeras while the other patients were mixed chimeras in one or more lineages. At a median follow-up of 9 months (range 3 to 29 months), 33 patients remain alive in complete remission or with no evidence of disease progression. Seven patients relapsed or progressed post-transplantation, and 4 of them subsequently died. Four patients died of regimen-related complications. There were no cases of grades III-IV acute GVHD. Only 2 patients developed grade II acute GVHD, and only 1 had chronic GVHD. The estimated probability of nonrelapse mortality was 11%. Although longer follow-up is needed to establish the long-term remission rates, this study demonstrates that this nonmyeloablative preparative regimen is associated with durable engraftment, minimal toxicity, and low incidence of GVHD.

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Salvage HLA-haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide for graft failure in non-malignant disorders

Bone Marrow Transplantation ◽

10.1038/s41409-021-01323-9 ◽

2021 ◽

Author(s):

Michael H. Albert ◽

Mehtap Sirin ◽

Manfred Hoenig ◽

Fabian Hauck ◽

Catharina Schuetz ◽

...

Keyword(s):

T Cell ◽

Graft Failure ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Reduced Intensity Conditioning ◽

Post Transplantation ◽

Hematopoietic Stem ◽

Reduced Intensity

AbstractGraft failure requires urgent salvage HSCT, but there is no universally accepted approach for this situation. We investigated T-cell replete haploidentical HSCT with post-transplantation cyclophosphamide following serotherapy-based, radiation-free, reduced intensity conditioning in children with non-malignant disorders who had rejected their primary graft. Twelve patients with primary or secondary graft failure received T-cell replete bone marrow grafts from haploidentical donors and post-transplantation cyclophosphamide. The recommended conditioning regimen comprised rituximab 375 mg/m2, alemtuzumab 0.4 mg/kg, fludarabine 150 mg/m2, treosulfan 20–24 g/m2 and cyclophosphamide 29 mg/kg. After a median follow-up of 26 months (7–95), eleven of twelve patients (92%) are alive and well with complete donor chimerism in ten. Neutrophil and platelet engraftment were observed in all patients after a median of 18 days (15–61) and 39 days (15–191), respectively. Acute GVHD grade I was observed in 1/12 patients (8%) and mild chronic GVHD in 1/12 patients (8%). Viral reactivations and disease were frequent complications at 75% and 42%, respectively, but no death from infectious causes occurred. In summary, this retrospective analysis demonstrates that a post-transplantation cyclophosphamide-based HLA-haploidentical salvage HSCT after irradiation-free conditioning results in excellent engraftment and overall survival in children with non-malignant diseases.

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Rapid Immune Reconstitution after a Reduced-Intensity Conditioning Regimen and a CD3-Depleted Haploidentical Stem Cell Graft for Pediatric Refractory Hematologic Malignancies.

Blood ◽

10.1182/blood.v108.11.5311.5311 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5311-5311

Author(s):

Xiaohua Chen ◽

Gregory A. Hale ◽

Raymond C. Barfield ◽

Ely Benaim ◽

Wing H. Leung ◽

...

Keyword(s):

Stem Cell ◽

Nk Cells ◽

Immune Reconstitution ◽

Acute Gvhd ◽

Conditioning Regimen ◽

Hematologic Malignancies ◽

Reduced Intensity Conditioning ◽

Hematopoietic Stem ◽

Reduced Intensity Conditioning Regimen ◽

Reduced Intensity

Abstract Haploidentical hematopoietic stem cell transplantation (HaploHSCT) from a mismatched family member (MMFM) donor offers an alternative option for patients who lack an HLA-matched donor. The main obstacles to successful haploidentical hematopoietic stem cell transplantation from a mismatched family member donor are delayed immune reconstitution, vulnerability to infections, and severe graft-versus-host disease (GvHD). Method: We designed a reduced-intensity conditioning regimen that excluded total body irradiation and anti-thymocyte globulin. The graft was immunomagnetically depleted of CD3+ T-cells (CD3 negative selection) and contained a large number of both CD34+ and CD34− stem cells and most other immune cells especailly NK cells. This protocol was used to treat 22 pediatric patients with refractory hematologic malignancies. Results and Discussion: After transplantation, 91% of the patients achieved full donor chimerism. They also showed rapid recovery of CD3+ T-cells, T-cell receptor excision circle counts, TCRβ repertoire diversity and NK-cells during first four months post-transplantation. The incidence and extent of viremia were limited and no lethal infection was seen. Only 9% of patients had grade 3 acute GvHD, while 27% patients had grade 1 and another 27% had grade 2 acute GvHD. This well-tolerated regimen appears to accelerate immune recovery and shorten the duration of early post-transplant immunodeficiency, thereby reducing susceptibility to viral infections. Rapid T-cell reconstitution, retention of NK-cells in the graft, and induction of low grade GvHD may also enhance the potential anti-cancer immune effect.

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Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia Using Alemtuzumab and Cyclophosphamide as Conditioning Regimen.

Blood ◽

10.1182/blood.v114.22.3198.3198 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3198-3198

Author(s):

Fernanda Lodi ◽

Gustavo Teixeira ◽

Antonio Vaz Macedo ◽

Rosana Lamego ◽

Simone Silva Magalhaes ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Aplastic Anemia ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Median Number ◽

Off Label Use ◽

Hematopoietic Stem ◽

Off Label

Abstract Abstract 3198 Poster Board III-135 Introduction Cyclophosphamide (Cy) with/without antithymocyte globulin (ATG) as conditioning regimen for allogeneic hematopoietic stem cell transplantation (AlloHSCT) is the treatment of choice for young patients with severe aplastic anemia (SAA). In developing countries, and particularly in Brazil, ATG costs limit its use in AlloHSCT for SAA patients. Alternative low-cost regiments, like busulfan (BU) with Cy as conditioning regimen is still associated with a significant rate of rejection, especially in heavily transfused patients, and long-term infertility. Alemtuzumab (Cam) was reported as an alternative to ATG for SAA patients, with similar activity and a lower cost. Material and Methods In order to study the effect of the combination of Cy and Cam, we reviewed all AlloHSCT performed for SAA using this conditioning regimen. Between April 2007 and Mai 2009, fifteen patients with SAA (defined by Camitta criteria) underwent an AlloHSCT in our institution. Median age at transplantation was 25 (range 5-42) years. All but one patient had positive CMV serology. Median number of transfusions was 20 (range 10-67). One patient received a second AlloHSCT due to a late (> 4 years) graft rejection. Patients received an unmanipulated bone marrow (n=11) or peripheral blood (n=4) graft as stem cell source and all but one patient were transplanted with an HLA-identical sibling. Median number of nucleated cell infused was 2.86 (range 1.65-6.50)x10 8/kg. Cyclosporin alone (n=10) or in combination with methotrexate (n=5) was used as GVHD prophylaxis. Results Thirteen out of 15 patients presented neutrophil recovery with a median time to > 0.5×10 9 neutrophil/L of 23 (range 13-30) days. Platelet recovery (> 20×10 9 platelets/L) occurred in thirteen patients with a median time of 16.5 (range 9-45) days. Acute graft versus host disease (GVHD) was observed in just one patient (grade II). None of 12 patients alive 100-days after AlloHSCT presented chronic GVHD. Seven patients presented CMV reactivation. One patient did not engrafted and other presented a late (14 months) rejection. One patient became pregnant after alloHSCT and gave birth to a healthy child. With a median follow-up of 315(range 4-782) days, two patients died and the estimate 1-year overall survival rate is 87%. One patient died due to complications of a CNS bleeding that occurred hours before marrow infusion and the other of GI infection while still on neutropenia. Conclusion Use of cyclophosphamide and alemtuzumab as conditioning regimen is a valid option in SAA patients undertaking AlloHSCT, with significant lower rates of acute and chronic GVHD. Nevertheless, a longer follow-up is required to properly evaluate rejection incidence. Disclosures Off Label Use: Drug: Alemtuzumab Off-label Use: Aplastic Anemia.

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Re-Exposure of Cord Blood (CB) to Non-Inherited Maternal HLA Antigens (NIMA) Improves Transplant Outcome in Patients (pts) with Hematologic Malignancies and May Reduce Relapse.

Blood ◽

10.1182/blood.v114.22.661.661 ◽

2009 ◽

Vol 114 (22) ◽

pp. 661-661

Author(s):

Jon J van Rood ◽

Cladd E Stevens ◽

Jacqueline Smits ◽

Carmelita Carrier ◽

Carol Carpenter ◽

...

Keyword(s):

Conflicts Of Interest ◽

Chronic Gvhd ◽

Hla Antigens ◽

Human Leukocyte ◽

Hematologic Malignancies ◽

Hematopoietic Stem ◽

Leukocyte Antigens ◽

Grade Ii ◽

The Impact ◽

Related Mortality

Abstract Abstract 661 CB hematopoietic stem cell transplantation (CBT) can be successful even if donor and recipient are not fully matched for human leukocyte antigens (HLA). This may result, at least in part, from tolerance-inducing events during pregnancy, but this concept has not been tested to date. Hence we analyzed the impact of fetal exposure to NIMA of the HLA-A, -B antigens or -DRB1 alleles on the outcome of 1121 pts with hematologic malignancies. All pts received single CB units provided by the NYBC, for treatment of ALL (N=451), AML (N=376), CML (N=116), MDS (N=79), other (N=99); 22% were transplanted in advanced stage. Median age was 9.7 years (range: 0.1-67); 29% of recipients were >16 years. Most pts (96%) received myeloablative cytoreduction. Sixty-two pts received fully matched grafts while 1059 received units mismatched (MM) for one or two HLA antigens. Of these, 79 (7%) had a MM antigen which was identical to a donor NIMA (Example: Pt: A1, A3; CBU: A1, A2; mother-CBU: A1, A3; A3 is NIMA). NIMA match was found in 25 recipients with one HLA MM and 54 of those with two MM. The NIMA match was identified after the transplant and was not used in unit selection. In multivariate analyses, NIMA matched transplants (NMTs), showed faster neutrophil recovery (RR=1.3, p=0.043), even for grafts with cell dose <3×107 (RR=1.6, p=0.053). There was no difference in the incidence of acute (grade II-IV) or chronic GvHD. 3-year relapse risk (cumulative incidence 22%) was reduced compared to 1 or 2 HLA MM no NIMA matched transplants, especially in pts with myelogenous malignancies given units with 1 HLA MM (RR=0.2, p=0.074). Further, 3-year transplant-related mortality was reduced (RR=0.7, p=0.034), particularly in pts ≥5 years old (RR=0.5, p=0.006), as was the 3-year overall mortality (RR= 0.7, p=0.029 and RR=0.6, p=0.015, respectively). As a result, in the NMTs, treatment failure (relapse or death) was significantly lower, particularly in pts ≥5 years (RR=0.7, p=0.019) and DFS was significantly improved (figure) and was similar to that of the 0 HLA MM group. These findings are the first indication that donor exposure to NIMA can improve post-transplant survival in unrelated CBT and might reduce relapse. We propose to include the NIMA of CB units in search algorithms. Thus, for pts lacking fully HLA matched grafts, HLA MM but NIMA matched CB units could be selected preferentially, since no adverse effects were seen. This strategy of selecting HLA MM grafts with optimal outcome effectively “expands” the current CB Inventory several-fold.Patient GroupNRR(95% Cl)p value0 MM360.5(0.3–0.8)0.0051 MM / NIMA Match180.4(0.2–0.9)0.0262 MM / NIMA Match400.8(0.5–1.2)0.3091 MM / No NIMA Match229reference group2 MM / No NIMA Match4871.1(0.9–1.3)0.365 Disclosures: No relevant conflicts of interest to declare.

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