Low Incidence of Acute Graft-VS.-Host Disease (GVHD) Using Tacrolimus (TAC) and Mycophenolate Mofetil (MMF) after Matched Sibling Donor (MSD) Non-Myeloablative Stem-Cell Transplants (NST) Conditioned with Fludarabine (FLU) and Low-Dose Total Body Irradiation (TBI).

Abstract Randomized studies after conventional allografting showed that in combination with methotrexate TAC was superior to cyclosporine for prevention of acute GVHD. Using the Seattle conditioning regimen of FLU/low-dose TBI we evaluated TAC/MMF as a substitute for cyclosporine/MMF as post-grafting immunosuppression after MSD PBPC NST. Thirty-two patients (median age 57, range 32–68 years), who were poor candidates for a conventional myeloablative transplant, were enrolled. Patient diagnoses included lymphoma (N=12) (7 follicular, 2 transformed, 1 mantle-cell, 1 diffuse large cell, 1 NK), myeloma (N=12), high-grade MDS (N=5), AML (N=2), Hodgkin’s (N=1). Patients were conditioned with FLU (30 mg/m2/d x 3), TBI (200 cGy), were infused donor PBPCs on day 0, and received GVHD prophylaxis with TAC (0.06 mg/kg PO b.i.d. from day −3), targeting initially 10–20 ng/mL, and MMF (15 mg/kg PO b.i.d., from day 0 to +27, discontinued without taper). TAC was tapered from day +100 to +180 and from day +35 to +56, in those patients with indolent (N=25) and aggressive malignancies (N=7), respectively. Regimen toxicities and myelosuppression were mild, allowing 75% of patients to have entirely outpatient transplantations. One patient (3%) experienced a non-fatal graft rejection. The % patients with mixed/donor T-cell chimerism were as follows: 1 month: 77%/23%, 3 mo: 86%/14%, and 1 yr: 20%/80%. Five patients (15.6%) experienced stage II–IV acute GVHD, presenting at median day +61. Eleven patients (34%) experienced chronic GVHD (1 limited, 10 extensive) at median onset day +190. In 6 of those patients (22%), chronic CVHD was not elicited by immunosuppression withdrawal or DLI upon tumor progression. Day+100 transplant-related mortality (TRM) was 0%. Overall TRM was 9%, with 3 deaths from GVHD-related multiorgan failure on days +105, +343, and +354, respectively. At median follow-up of 19 (2–41) months, 20 patients (62.5%) were alive, 17 patients (53%) remained progression-free, 13 of them (41%) in complete remission. Median progression-free and overall survival times were 21 and 33 months, respectively. Conclusion: TAC/MMF after a MSD NST provides effective acute GVHD prophylaxis, and is associated with an excellent early safety profile. As compared to reported outcomes with cyclosporine/MMF, acute GVHD incidence appeared lower and onset was delayed.

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Sirolimus, Tacrolimus and Reduced-Dose Methotrexate as Graft Versus Host Disease (GVHD)Prophylaxis after Non-Myeloablative Stem Cell Transplantation: Low Incidence of Acute GVHD Compared with Tacrolimus/Methotrexate or Cyclosporine/Prednisone.

Blood ◽

10.1182/blood.v104.11.730.730 ◽

2004 ◽

Vol 104 (11) ◽

pp. 730-730 ◽

Cited By ~ 3

Author(s):

Edwin P. Alyea ◽

Shuli Li ◽

Haesook Kim ◽

Corey Cutler ◽

Vincent Ho ◽

...

Keyword(s):

Serum Level ◽

Low Dose ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Peripheral Blood Stem Cells ◽

Dose Methotrexate ◽

Gvhd Prophylaxis ◽

Low Incidence

Abstract Sirolimus (rapamycin) is a macrocyclic lactone similar in structure to tacrolimus and cyclosporine (CSA) but with a distinct mechanism of action. Sirolimus binds to both FKBP12 and mTOR and inhibits signal transduction and cell cycle progression. The drug is synergistic with tacrolimus but has a distinct toxicity profile, thereby allowing their use in combination. We report results of a phase II trial combining sirolimus with tacrolimus and low-dose methotrexate (MTX) as GVHD prophylaxis in matched related and unrelated donor NST. Results of this trial were compared with patients who had previously undergone NST receiving tacrolimus/MTX alone or CSA/prednisone(pred). All patients received fludarabine (30 mg/m2/d x 4days) and intravenous busulfan (0.8mg/kg/d x 4 days) as conditioning. All patients received G-CSF mobilized peripheral blood stem cells with a targeted cell dose of 1 x 107 CD34+ cells/kg. G-CSF 5 mcg/kg was started on day 1. Sirolimus containing GVHD prophylaxis included sirolimus 12 mg loading dose on day −3 and then 4 mg po qd targeting a serum level of 3–12 ng/ml. Tacrolimus was initiated at 0.05 mg/kg po b. i.d. beginning day −3 with a targeted serum level of 5–10 ng/ml. MTX (5 mg/m2) was given days, 1, 3 and 6. Planned taper of the GVHD medications was ~30% at days 60, and 120 with discontinuation by day 180. The median follow up is 14 months for patients receiving sirolimus and all evaluable patients have been followed for >100 days. 40 patients have been transplanted, 20 from related and 20 from unrelated donors. The median age was 57 years (range 20–69). Diseases included: NHL (9), MDS (7), Hodgkin’s disease (6), CLL (6), AML(5), CML (5), MM (1) and CMML(1). 18 patients (45%) had received prior myeloablative transplantation. 31 patients (78 %) had advanced disease at the time of transplantation. Patients receiving tacrolimus/MTX (n=36) and CSA/pred (n=49)had similar characteristics. Sirolimus was well tolerated and no severe adverse events related to the drug were noted. Acute grade 2–4 GVHD was significantly reduced in patients receiving sirolimus/tacrolimus/MTX, 8% vs 18% in patients receiving tacrolimus/MTX and 37% in those receiving CSA/Pred (p=0.003). Time to neutrophil engraftment was slower in methotrexate containing regimens (13 days vs 9 days, p=0.01), but there was no difference between sirolimus/tacrolimus/MTX and tacrolimus/MTX alone. Median donor derived hematopoiesis, measured 1–2 months after transplant, was high in all groups (sirolimus/tacrolimus/MTX 91%, tacrolimus/MTX 95% and CSA/pred 90%, p=0.91). The 1 year overall survival was sirolimus/tacrolimus/MTX 71%, tacrolimus/MTX 48% and CSA/pred 45% (p=0.17). 1-year progression free survival was 49%, 27% and 37%, respectively (p=0.11). The addition of sirolimus to tacrolimus and low dose MTX is well tolerated and is associated with a low incidence of acute GVHD. The addition of sirolimus does not delay engraftment compared with tacrolimus/MTX and results in a similar high level of donor derived hematopoiesis. Further patient accrual and longer follow-up is needed to yield information on the incidence of chronic GVHD and overall outcome.

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Bone marrow transplantation in Fanconi anemia using matched sibling donors

Blood ◽

10.1182/blood.v84.6.2050.2050 ◽

1994 ◽

Vol 84 (6) ◽

pp. 2050-2054 ◽

Cited By ~ 57

Author(s):

M Kohli-Kumar ◽

C Morris ◽

C DeLaat ◽

J Sambrano ◽

M Masterson ◽

...

Keyword(s):

Bone Marrow ◽

Fanconi Anemia ◽

Low Dose ◽

Chronic Gvhd ◽

Graft Versus Host ◽

Gvhd Prophylaxis ◽

Feasible Option ◽

Matched Sibling ◽

Low Incidence

Abstract Eighteen patients with Fanconi anemia (FA) with evidence of bone marrow (BM) aplasia underwent allogenic BM transplants (BMT) from matched sibling donors (MSD). Median age at BMT was 7.6 years. Conditioning consisted of low-dose cyclophosphamide (CY; 5 mg/kg x 4 days) and thoracoabdominal irradiation (TAI; 400 cGy). Graft-versus-host disease (GVHD) prophylaxis included cyclosporin A and prednisone. In addition antithymocyte globulin (ATG) was administered in the pretransplant period to promote engraftment and in the posttransplant period for additional GVHD prophylaxis. Engraftment occurred rapidly (median, 12 days for an absolute neutrophil count > or = 0.5 x 10(9)/L; median, 22 days for platelet count > or = 50 x 10(9)/L). Seventeen patients have sustained engraftment and are transfusion-independent, with Lansky scores of 100% at median follow-up of 27 months. One patient developed graft failure 4 months after initial engraftment and required a second BM infusion. None of the patients developed acute GVHD; 3 patients (16%) developed chronic GVHD. BMT is a feasible option for FA patients having an MSD and should be performed at a young age and early in the course of the disease, before the development of complications. We believe the addition of ATG to the transplant regimen of low-dose CY, TAI, and cyclosporin was responsible for improvement in the survival of FA patients undergoing BMT. The regimen was well tolerated and was associated with a low incidence of complications including GVHD.

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A Randomized, Controlled Trial of Graft-Versus-Host Disease (GVHD) Prophylaxis Comparing Tacrolimus and Mycophenolate Mofetil to Tacrolimus and Methotrexate: Analysis of GVHD, Relapse and Survival.

Blood ◽

10.1182/blood.v112.11.2235.2235 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2235-2235 ◽

Cited By ~ 1

Author(s):

Janelle Perkins ◽

Melissa Alsina ◽

Claudio Anasetti ◽

Ernesto Ayala ◽

Hugo F. Fernandez ◽

...

Keyword(s):

Overall Survival ◽

Randomized Controlled Trial ◽

Mycophenolate Mofetil ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Controlled Trial ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Randomized Controlled ◽

Gvhd Prophylaxis

Abstract The selective IMPDH inhibitor, mycophenolate mofetil (MMF), has entered the clinic with the promise to provide potent immune suppression without the side effects of methotrexate (MTX) or other broad-spectrum immunosuppressants. The use of MMF in the prevention of GVHD after hematopoietic cell transplantation (HCT) has been increasing worldwide, but only one small controlled study comparing cyclosporine + MMF to cyclosporine + MTX has been conducted to date. We compared GVHD prophylaxis with tacrolimus + MTX (TAC/MTX) to tacrolimus + MMF (TAC/MMF) in a single institution, randomized, controlled trial. Eligible patients were to receive T-replete peripheral blood HCT from 10/10 or 9/10 HLA-A, B, C, DRB1 and DQB1 matched donors, and have no contraindications to the use of TAC, MTX, or MMF. Randomization was stratified based on conditioning regimen intensity. Ninety-two pts were randomized, 45 to TAC/MMF and 47 to TAC/MTX and were all included in the intent-to-treat (ITT) analysis. Two pts were not transplanted and one pt withdrew consent prior to transplant. These pts were all randomized to TAC/MMF and excluded in the modified ITT (MITT) analysis. Pts received TAC 0.03 mg/kg/24hr as a continuous IV infusion beginning day -3 with doses adjusted to maintain whole blood levels of 5–15ng/ml. Pts were converted to PO therapy as tolerated and tapered after 6 months in the absence of GVHD. MTX was given IV at doses of 15mg/m2 day +1 and 10mg/m2 on days +3, +6 and +11. In pts with renal insufficiency, MTX doses were adjusted per pts’ pretransplant creatinine clearance. MMF was dosed at 15 mg/kg every 12 hours (up to 3g/d) IV beginning day 0, switched to PO as tolerated and continued for 12 months. Acute GVHD was graded weekly by Thomas’ criteria, modified per ASBMT consensus criteria; chronic GVHD was scored monthly based on NIH consensus criteria. The groups were balanced with respect to age, diagnosis, disease risk, recipient/donor CMV status, conditioning regimen, donor type and relation. The incidences of grade 2–4 and 3–4 acute GVHD were 79% and 4% in the TAC/MTX arm and 79% and 17% in the TAC/MMF arm (p=1.0 and 0.08, respectively). The incidence of moderate or severe chronic GVHD was 55% in the TAC/MTX arm and 59% in the TAC/MMF arm (p=0.91). By ITT analysis, the cumulative incidence of non-relapse mortality suggested an early difference in favor of TAC/MTX, but at 2 years it was 28% for TAC/MTX arm compared to 32% for the TAC/MMF arm (p=0.41; MITT p=0.33). The cumulative incidence of relapse was 33% in TAC/MTX arm compared to 18% (ITT; 16% MITT) for the TAC/MMF pts (p=0.06; p=0.04 MITT). Overall survival was similar between groups in both the ITT (p=0.76; 62% TAC/MTX vs. 66% TAC/MMF at 1 year) and MITT analysis (p=0.75; 62% TAC/MTX vs. 66% TAC/MMF at 1 year). We conclude that MMF was no better than MTX in preventing acute or chronic GVHD and may perhaps be less effective in preventing more severe forms of acute GVHD. Given the direction of effect we observed in severe acute GVHD, it is unlikely that a larger trial would show benefit for this endpoint. There was a strong suggestion that relapse of malignancy was more frequent after MTX than MMF, apparently in relation to the drug interference with the graft-vs.-leukemia effect. The beneficial effect of MMF on relapse was offset by the early increase in nonrelapse mortality, so that overall survival was unaffected.

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One Antigen HLA-Mismatched Related and 8/8 Allele Matched Unrelated Donors Are Associated with Similar Survival after Hematopoietic Cell Transplantation for Acute Leukemia.

Blood ◽

10.1182/blood.v112.11.965.965 ◽

2008 ◽

Vol 112 (11) ◽

pp. 965-965

Author(s):

David Valcarcel ◽

Fangyu Kan ◽

Tao Wang ◽

Stephanie J. Lee ◽

Stephen R Spellman ◽

...

Keyword(s):

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Unrelated Donor ◽

Free Survival ◽

Gvhd Prophylaxis ◽

Unrelated Donors ◽

Related Donor ◽

Disease Free

Abstract Patients in need of an allogenetic hematopoietic cell transplant but who lack an HLA genotypically identical sibling donor, are faced with the decision to consider a single HLA antigen mismatched related donor, or a search for a suitable 8/8 matched unrelated donor. We compared the outcomes of adult patients (≥18 years old) receiving a transplant for the treatment of AML or ALL in first or second remission from either a one-antigen mismatched related donor (MMRD group, N=89) reported to the CIBMTR or an 8/8 HLA-A, B, C and DRB1 allele matched unrelated donor (UD group, N=700) facilitated by the NMDP between 1995–2005. MMRD group was typed by serological or DNA-based methods for HLA-A, -B and –DR with all results verified by lab report review. The UD group was retrospectively typed for HLA-A, B, C and DRB1 by high resolution typing methods. Most received myeloablative conditioning regimens (77%), calcineurin inhibitor-based GVHD prophylaxis (100%) and T cell replete grafts (100%). 13% received ATG with the conditioning regimen. Median follow-up was 54 and 38 months in the MMRD and UD groups, respectively. The MMRD group was younger (median age 35 vs 43, p=0.002), had more ALL patients with low-risk cytogenetics (43% vs 18%, p=0.005), had older donors (median age: 38 vs 34, p=0.047), were more likely to receive methotrexate for GVHD prophylaxis (89% vs 77%, p=0.014) and were more likely to be transplanted prior to 2001 (62% vs 24%; p<0.001). There were no differences in patient or donor gender, diagnosis, disease-status, cytogenetic-risk of AML, time from diagnosis to transplant, stem cell source, conditioning regimen, use of ATG and Karnofsky index. Univariate comparisons (MMRD vs. UD) showed: 3-year OS (42% vs 44%, p=0.647), 3-year DFS (41% vs 41%, p=0.931), 3-year TRM (39% vs 31%, p=0.136), 3-year incidence of relapse (20% vs 28%, p=0.094), grade III–IV acute GVHD by 100 days (22% vs. 15%, p=0.147), chronic GVHD by 1 year (35% vs 47%, p=0.029). All multivariate analyses were adjusted for patient and transplant characteristics and are shown in the table below. In summary, transplants utilizing one-antigen mismatched related and 8/8 allele-matched unrelated donors did not significantly differ in overall survival or disease free survival, but chronic GVHD was more frequent after UD transplantation. Outcome RR (MMRD vs. UD) 95% CI p-value Survival 0.99 0.73–1.34 0.94 Disease-free survival 1.06 0.80–1.41 0.69 Treatment related mortality 1.14 0.77–1.69 0.52 Relapse 0.81 0.50–1.30 0.38 Acute GVHD III–IV 1.53 0.91–2.57 0.11 Chronic GVHD 0.58 0.39–0.85 0.006

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Fludarabine and Busulfan (FluBuP Regimen) as Myeloablative Conditioning Regimen for Allogeneic PBSCT in 71 Leukemic Patients (A Unicenteric Study).

Blood ◽

10.1182/blood.v104.11.5156.5156 ◽

2004 ◽

Vol 104 (11) ◽

pp. 5156-5156

Author(s):

Masoud Iravani ◽

Maryam Tavakoli ◽

Ahmad Reza Shamshiri ◽

Mohammad Reza Evazi ◽

Asadollah Mousavi ◽

...

Keyword(s):

Acute Gvhd ◽

Hemorrhagic Cystitis ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Cmv Infection ◽

Platelet Recovery ◽

Low Incidence ◽

Reduced Toxicity

Abstract Following 3 other centers in USA, Canada and Germany, we are evaluating fludarabine (40 mg/m2 on days −6 to −2) and busulfan (4 mg/kg/day on days −5 to −2) as a new conditioning regimen for allogeneic peripheral blood stem cell transplantation in leukemic patients with matched related donors. Seventy one patients were enrolled, 18 with high and 53 with standard risk (18 ALL, 35 AML, 16 CML and 2 MDS; F=29 M=42). The median patient age was 23.7 years(range, 2.4– 46.7). Cyclosporine was used as a prophylactic agent for GVHD (3mg/kg IV till +4, 10 mg/kg oral from day +5). The median follow-up was 269 days (range, 50–459 days). 91.5% and 15.5% developed mucositis and hepatic toxicity respectively which resolved with conservative therapy. There was no cardiac toxicity (except one patient with mild pericardial effusion and another with tachycardia). The median of highest serum creatinin level during hospitalization were 1.6 mg/dl (range, 0.8–3.7; 24.3% with Cr>2) and serum cyclosporine level, at the same time, was 246 ng/ml (range, 9–814). 7% experienced hemorrhagic cystitis (infection was ruled out) and 36.6% experienced moderate to severe headache. 38% and 14.1% of the patients showed grade 1, 2 and grade 3 acute GVHD respectively. Grade 4 acute GVHD was found in one patient. 50% and 6% showed limited and extensive chronic GVHD. 27% of patients became CMV+ (min +17, max +69). The median time for neutrophil and platelet recovery were 10 (min 0, max +26) and 12 (min 0, max +30) days. In day +38, 86.7% of the patients had 90% or more, mononuclear chimerism (with STR-PCR technique; median, 97%; range, 25–100). 5 ALL and 8 AML patients relapsed (18.3% of all patients) and 6 (8.45%) died after relapse. Nonrelapse mortality was 13% (9 patients; acute GVHD grade IV=1, CMV infection and GVHD=2, CMV infection=2, pneumonia=2, infection=2). With a median follow up of 9 months (range, 1.6–15.3 months), the probability of overall survival and disease free survival were 79.68% and 81.26% respectively. It could be beneficial to use fludarabine versus cyclophosphamide in standard conditioning regimen for leukemic patients because of reduced toxicity, low incidence of acute GVHD and facilitated donor engraftment.

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Outcome of Busulfan and Fludarabine-Based Reduced Intensity Conditioning Regimen for Related and Unrelated HSCT in Fanconi Anemia Patients

Blood ◽

10.1182/blood.v118.21.1964.1964 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1964-1964

Author(s):

Saba Azarnoush ◽

Raphael Porcher ◽

Regis Peffault de la Tour ◽

Karima Yakouben ◽

Benedicte Bruno ◽

...

Keyword(s):

Bone Marrow ◽

Low Dose ◽

Acute Gvhd ◽

Bone Marrow Failure ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Secondary Malignancy ◽

Secondary Malignancies ◽

Reduced Intensity

Abstract Abstract 1964 Rationale: HSCT is the only curative treatment for Fanconi Anemia (FA) pts with either bone marrow failure or MDS/Leukemia. Due to characteristic chromosomal instability, the poor outcome of FA pts transplanted after so-called conventional myelo-ablative conditioning regimen has been proved. Then, reduced-intensity conditionning regimen (RIC) has been considered for years as a model for allogeneic HSCT in FA pts. The use of fludarabine-based cond' regimen from about 2000 increased dramatically the overall survival of FA pts. Different Flu-based RIC were developed. Patients and method: Between Feb'02 and Dec'10, 17 FA pts from 3 academic French centers were included: 11 from R. Debre hospital, 5 from St Louis hospital and 1 from J. de Flandre hospital. All pts underwent HSCT because of bone marrow failure. They presented no MDS or leukemia. All time-to-event outcomes were counted from the date of HSCT to the date of event or date of last follow-up, except acute GVHD that was arbitrarily censored at 200 days. Death was considered as a competing risk in analyses of neutrophil and platelet recovery and chronic and acute GVHD. Overall survival was estimated using Kaplan-Meier product-limit estimator. For competing risks analyses, cumulative incidences were estimated using usual methodology. Results: Median age at diagnosis and at HSCT were 4.7 years (range 1,8-9,3) and 7,4 years (range 4,4-15,2), respectively. 12 pts presented with less than 3 FA-related malformations and 5 with more than 3 malformations. 2 patients received more than 20 transfusions before HSCT, whereas 8 pts received less than 20 transfusions and 7 patients did not received any. 2 patients received androgen therapy before HSCT. All patients received the same RIC i.e. fludarabine 30mg/m2/d × 3d, cyclophosphamide 10mg/kg/d × 4d and IV busulfan (Bu) 0.75 of body weight- adjusted recommended dose (equivalent to 6.4mg/kg total dose of oral Bu). This RIC did not contain any irradiation. Graft versus-host disease (GvHD) prophylaxis consisted of CSA associated with MMF or corticosteroids. Donors were either matched related (sibling, n= 6; other, n=2) or unrelated (10/10, n= 6; 9/10, n= 3). Stem cell sources were BM (n=10), UCB (n=4) and PBSC (n=2). 9 out of 17 pts had a donor from the same gender whereas 4 male recipients received transplant from female donor. CMV status were −/−, −/+, +/− and +/+ for 8, 4, 1 and 4 D/R pairs, respectively. Median follow-up was 32 months (range 3–102). Successful engraftment was obtained in all patients with a median time for neutrophil recovery of 17 days (range 10–42). All patients presented with 100% donor chimerism. One patient experimented secondary graft failure and died at D291 from infection and renal failure. During transplant procedure, 13 pts experimented at least one severe infectious complication (staphylococcus n=2; pseudomonas n=1; aspergillus n= 2; candida n=2; viral reactivation n= 13). 1 pt presented with moderate hepatic veno-occlusive disease. Five pts died from TRM and 12 pts remained alive in a good health condition. 36 month OS was 69% (95%CI 50 to 96). Cumulative incidence of grade 2 to 4 acute GVHD was 71% (95%CI: 41–87). 5 pts presented with either limited (n=4) or extensive (n=1) chronic GvHD and 36 month cumulative incidence of chronic GVHD was 33% (95%CI 11 to 58). To date, no pt had secondary malignancy. Discussion: Our study confirms the good results obtained by other groups when using flu-based RIC in FA pts. Indeed, satisfying engraftment and long-time survival rates were obtained without any TBI, irrespective of the stem cell source and the donor type. However, we have a concern regarding the cGVHD rate we obtained. As demonstrated by an on-going study of EBMT registry, the risk of secondary malignancy in these pts is statistically correlated to cGvHD. Then, this rate still remains probably too high in our study, even though only one pt presented with extensive cGvHD and no pts developed any secondary malignancy. But this could be explained by the short follow-up. Suppression of one alkalyting agent may reduce both cGVHD incidence and other tissue injuries leading to secondary malignancies. Then, we claim for suppression of Bu for related donor HSCT. In FA pts receiving transplant from unrelated donor, the relative impact of either low-dose IV-Bu – as we used here - or low-dose irradiation on toxicity and especially development of secondary malignancies remains to be evaluated. Disclosures: No relevant conflicts of interest to declare.

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Impact of Modifying Conditioning and Immunosuppressive Strategies in Allogeneic Hematopoietic Stem Cell Transplantation in Children with Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2019-122988 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5714-5714

Author(s):

Nawar Dakhallah ◽

Mylène Beauchemin ◽

Johanne Richer ◽

Sonia Cellot ◽

Pierre Teira ◽

...

Keyword(s):

Stem Cell ◽

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Acute Gvhd ◽

Lymphoblastic Leukemia ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Current Approach ◽

Hematopoietic Stem ◽

Gvhd Prophylaxis

Background:Hematopoietic stem cell transplants (HSCT) is indicated for some very high-risk childhood acute lymphoblastic leukemia (ALL) patients in complete remission 1 (CR1) and for patients in >CR2. Relapse remains the most frequent complication after transplant. In 2012, in order to decrease the relapse rate, we modified our conditioning and GVHD prophylaxis regimen. Total body irradiation doses were increased, etoposide removed and fludarabine introduced. Anti-thymocyte globulin (ATG) was removed of GVHD prophylaxis regimen and mycophenolate mofetil was added for unrelated marrow grafts. The aim of this study was to compare outcome between previous (PS) and new strategies (NS) prior and after 2012. Methods: This retrospective study included all 47 patients aged 0 to 18 years old who underwent a first HSCT for ALL at Sainte-Justine University Health Center from 2007 to 2017. Our primary endpoint was 2-year event-free survival (EFS) between PS (n=22) and NS (n=25) groups. Secondary endpoints included overall survival (OS), relapse, GVHD, immunological recovery and infection rates. Results: Demographic parameters and leukemia characteristics were not significantly different between groups. In the PS group, median age was 6.1 years [2.7;13.5] and 41% of patients were female. In the NS group, median age was 7.1 years [2.4;11.4] and 44% of patients were female. B-cell and T-cell lineage leukemias were present in respectively 82% and 18% of PS and 76% and 24% in NS. Fourteen percent of patients were transplanted in CR1 in the PS versus 40 % in the NS group. EFS at 2 and 5 years were respectively 46% and 36% with the PS compared to 60% and 53% with the NS (p=0.170). OS at 5 years was significantly higher with the NS (46% vs 75%, p=0.05). Morphologic relapse rates at 5 years of PS and NS were 55% and 30% (p=0.14). Acute GVHD rate at 6 months was superior with the NS (41% vs 80%, p=0.002). Chronic GVHD rate at 5 years was similar between groups. At least one proven infection at 100 days was documented in 96% compared to 88% of patients with the PS and NS respectively (p=0.08). Neutrophil recovery at 60 days and platelets recovery at 180 days were not significantly different. T-cell Immune recovery at 6 months was superior in the NS. Median (min;max) CD3 counts in PS and NS were respectively 339 (132;1152) versus 946 (284;1944) (p=0.009), CD4 counts were 221 (65;612) versus 594 (238;920) (p=0.046) and CD8 counts were 55 (34;414) versus 320 (210;1104) (p<0.001). Conclusion: Compared to the PS, the NS of conditioning regimen and GVHD prophylaxis shows a significant improvement in OS and a tendency towards decreased relapse and increased EFS. However, we found a significant increase in acute GVHD with this regimen, which is explained by the removal of ATG from the regimen. These results highlight the necessity to adjust our strategy with HSCT ALL with the aim of maintaining graft versus leukemia effect without increasing GVHD. Emerging immunotherapy (such as antibody-based and chimeric antigen receptor T cell therapies) might shift the management of refractory and relapsed ALL and our current approach to HSCT. Disclosures Bittencourt: Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Travel, accommodations expenses.

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Low Dose Antithymocyte Globulin (ATG) for Graft-Versus-Host Disease (GVHD) Prophylaxis

Blood ◽

10.1182/blood.v128.22.5788.5788 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5788-5788 ◽

Cited By ~ 1

Author(s):

Anand Tandra ◽

Leland Metheny ◽

David Yao ◽

Paolo F. Caimi ◽

Lauren Brister ◽

...

Keyword(s):

Cumulative Incidence ◽

Lymphoproliferative Disorder ◽

Low Dose ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Hla Typing ◽

Viral Reactivation ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

Gvhd Prophylaxis

Abstract ATG appears to reduce the incidence of acute and chronic GVHD after allogeneic hematopoietic stem cell transplantation (HSCT). Potential risks of this strategy include viral reactivation, delayed immune recovery and increased relapse rates. The ideal dosing of rabbit ATG in this context is largely unknown. We therefore hypothesized that low dose ATG would reduce the incidence of acute and chronic GVHD in matched unrelated donor (MUD) transplants without compromising survival and relapse rate. A retrospective analysis was performed of a cohort of high-risk MUD HSCT recipients treated since year 2013, when our practice changed to include rabbit ATG at 3 mg/Kg for all MUD transplants at the Case Medical Center in Cleveland, Ohio. Herein we present the results of this analysis. Methods. 58 MUD transplants were performed between years 2013 and 2016, with a median follow up of 262 days post-transplant. All donor-recipient pairs were matched by high resolution HLA typing at HLA-A, -B, -C, and DRB1, (8/8 matches) with the exception of 4 pairs (7/8 matches. Median age was 56 years (range, 53-64). Underlying diagnoses were AML (n=26), MDS (13), CML (n=5), NHL (n=9), Hodgkin's lymphoma (n=2), Multiple Myeloma (n=1) and myeloproliferative disorders (n=2). Preparative regimens were ablative in 26 cases (45 %) and of reduced intensity in 31 cases (55 %). Graft source was bone marrow (n=5) and peripheral blood (n=53). All but 4 pts received GVHD prophylaxis with tacrolimus, and mini-methotrexate (5 mg/m2 on days +1, +3, +6 and +11), in addition to rabbit ATG 3 mg/Kg divided in two doses on days -2 and -1 pre HSCT. Cytomegalovirus (CMV), Epstein-Barr virus (EBV), and Human Herpes Virus (HHV6) PCR were conducted thrice weekly during the first 100 days after HSCT. Results. The 100-day cumulative incidence of grade II-IV acute GVHD was 41% (95% CI: 29-57; Fig 1), while the cumulative incidence of grade III-IV acute GVHD was 18% (95% CI: 9-35; Fig 2). 1-year cumulative incidence of chronic GVHD was 27% (95% CI: 17-42; Fig 3). At 180 days, the incidence of CMV viremia (defined as more than 1,000 copies/mL) was 25% (95% CI: 16-40), while the incidence of EBV and of HHV6 viremia was 35% (95% CI: 24-51) and 14% (95% CI: 8-27), respectively. There was no instance of EBV-related lymphoproliferative disorder. 3-year overall survival estimate is 48% (95% CI: 34-62). Cumulative incidence of Non-relapse mortality (NRM) and relapse at 1 year was 21% (95% CI: 12-37) and 44% (95% CI: 29-65), respectively. Conclusion. Our study shows that low dose rabbit ATG appears to reduce chronic GVHD rates without a major effect on acute GVHD incidence. CMV, EBV and HHV6 reactivation did occur, albeit at rates that are somewhat lower than those historically reported, without EBV-driven lymphoproliferative disorder. Disclosures Caimi: Genentech: Speakers Bureau; Roche: Research Funding; Novartis: Consultancy; Gilead: Consultancy.

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Alternative Donor Hematopoietic Stem Cell Transplantation for Sickle Cell Disease in Europe

Blood ◽

10.1182/blood-2018-99-111129 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4645-4645 ◽

Cited By ~ 2

Author(s):

Barbara Cappelli ◽

Graziana Maria Scigliuolo ◽

Fernanda Volt ◽

Selim Corbacioglu ◽

Josu de la Fuente ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Graft Failure ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Gvhd Prophylaxis ◽

Alternative Donor

Abstract Hematopoietic stem cell transplant (HSCT) from an HLA identical sibling is a well-established curative therapy for sickle cell disease (SCD). HSCT from an unrelated donor is a treatment option, but the likelihood of finding a donor varies according to ethnicity and results are still limited. HLA haploidentical relatives can be alternatively used but, to date, only small series of patients have been described. We report outcomes of patients (pts) transplanted with related haploidentical (Haplo) or unrelated (UD) donors grafts and reported to EBMT/EUROCORD databases. Sixty four pts transplanted in 22 EBMT centers between 1991 and 2017 were retrospectively analyzed. Pts were described according to the donor type: haploidentical (n=40) and unrelated (n=24) [adult UD n=19; cord blood (CB) n=5]. The objective of the study was to describe alternative donor transplants for SCD in Europe without performing comparison analyses due to the size and heterogeneity of the groups. Primary endpoint was 3-year overall survival (OS). Median follow-up (FU) was 28 months (range: 1.6-156) [29.5 months (range: 2.1 - 133.5) for Haplo and 24.6 (range: 1.6 - 156) for UD]. Median age at HSCT was 14.2 years (range: 3-31.7) in Haplo and 11.8 (range: 2.1-42.8) in UD, with a predominance of children (<16 years) in both groups (23/40 and 19/24, respectively). Before HSCT, 68% of overall pts were treated with hydroxyurea and 62% received more than 20 red blood cell (RBC) units. RBC alloimmunization occurred in 14% of transfused pts. In both groups, vaso-occlusive crisis and cerebral vasculopathy were the most frequent SCD complications and the main indications for HSCT. Other complications were acute chest syndrome (44%), liver disease (31%) and infection (23%). In Haplo, median year of transplant was 2014 (range: 1991-2017) and in UD 2011 (range: 2004-2015). In Haplo, two major protocols were used: (1) post -transplant cyclophosphamide (PTCY) with G-CSF primed bone marrow (BM) and a fludarabine+ cyclophosphamide+thiotepa+2Gy TBI conditioning regimen [16 pts and 2 centers performing most (n=13) of the transplants]; (2) a protocol (performed in 2 centers) consisting in the use of G-CSF mobilized peripheral blood stem cells (PBSC) with ex-vivo B and T cell depletion (BT depleted) (15 pts) and a fludarabine+thiotepa+ treosulfan conditioning regimen (14/15 pts). Haplo donors were most frequently the parents [mother (50%), father (29%), brother (14%) and cousin (7%)]. ATG was used in 95% of transplants and the most frequent combination for graft versus host disease (GvHD) prophylaxis was mycophenolate mofetil (MMF)+sirolimus in PTCY and MMF+ cyclosporine A (CSA) in BT depleted. In UD, graft source distribution was 14 BM, 5 PBSC and 5 CB. Conditioning regimens were mainly myeloablative (83%) with fludarabine+thiotepa+ treosulfan in 54% of HSCT. ATG was used in 87% and campath in 9% of transplants; GvHD prophylaxis was CSA and methotrexate in 50%. Neutrophil engraftment at 60 days was 95±4% in Haplo and 84±8% in adult UD, after a median engraftment time of 18 and 22 days, respectively. In Haplo, 7 pts experienced graft failure (3 primary and 4 late), of those 3 had a second allogeneic transplant and were alive at last FU, at 16, 16 and 63 months respectively; 1 patient died after rescue with autologous transplant and 3 were alive after autologous reconstitution. In adult UD, 3 pts had a primary and 1 a late graft failure, none of them had a second transplant and were all alive at last FU, at 2, 13, 28, 118 months respectively. Grade II-IV acute GvHD at 100 days was 25±7% in Haplo and 21±9% in adult UD; acute GvHD grade III-IV was observed in 3 pts in Haplo (none in BT depleted) and 2 pts in adult UD. Chronic GvHD was observed in 10 pts in Haplo (5 extensive, 3 of these in PTCY) and 3 pts in adult UD (2 extensive). OS at 3 years was 88±4%; being 89±5% in Haplo (88±8% for PTCY, 92±8% for BT depleted) and 94±5% in adult UD. 3-year event free survival was 58±7%; in detail, 60±9% in Haplo (56±12% for PTCY, 68±13% for BT depleted) and 60±12% in adult UD. Overall, 8 pts died (5 Haplo and 3 UD) due to infections or GVHD. Among the 5 pts receiving CB transplant 3 are alive (1 of which after graft failure and a second allogeneic transplant). Conclusion: This preliminary analysis shows that, despite an acceptable OS, rejection and chronic GvHD are still of concern; therefore alternative donor transplants for SCD should be performed in experienced centers with prospective clinical trials. Disclosures Pondarré: Blue Bird Bio: Honoraria; Novartis: Honoraria; Addmedica: Membership on an entity's Board of Directors or advisory committees. Zecca:Chimerix: Honoraria. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy. Bader:Medac: Patents & Royalties, Research Funding; Riemser: Research Funding; Neovii: Research Funding; Cellgene: Consultancy; Novartis: Consultancy, Speakers Bureau. Bernaudin:AddMedica: Honoraria; Pierre fabre: Research Funding; BlueBirdBio: Consultancy; Cordons de Vie: Research Funding.

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Thiotepa-Fludarabine-Treosulfan (TFT) Conditioning for 2nd Allogeneic Peripheral Blood Hematopoietic Cell Transplantation (HCT) from a Second Unrelated Donor in Patients with Acute Myeloid Leukemia (AML) Relapsed after Prior Allogeneic HCT: A Prospective Multicenter Phase II Trial

Blood ◽

10.1182/blood-2018-99-118999 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 210-210

Author(s):

Jürgen Finke ◽

Claudia Schmoor ◽

Matthias Stelljes ◽

Andreas Burchert ◽

Peter Dreger ◽

...

Keyword(s):

Primary Endpoint ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Unrelated Donor ◽

Allogeneic Hct ◽

Gvhd Prophylaxis ◽

Secondary Endpoints ◽

Full Analysis

Abstract Introduction: Relapse of AML after allogeneic HCT has a dismal prognosis. Long-term survival after 2nd allogeneic HCT has been described in selected patients. Here we tested a specific protocol with a fixed drug combination for myeloablative conditioning and GvHD prophylaxis for 2nd allogeneic HCT from a different unrelated donor. (EudraCT no.: 2012-005414-18, German Clinical Trials Registry no.: DRKS00005126) Methods : Aim of the trial was to show efficacy and safety of a 2nd alloHCT from an unrelated donor after a uniform conditioning with Treosulfan 3x12gm/m2, Fludarabin 3x30mg/m2, and Thiotepa 3x 5mg/kg (TFT), and GvHD prophylaxis with cyclosporine A (CyA) /Mycophenolate and ATG-F (Neovii) 3x10mg/kg. Eligible were adult patients with AML, ECOG ≤ 2, with sensitive or refractory hematologic relapse (≥ 20% blasts) > 6 months after a prior allogeneic HCT , including secondary (s) and/ or tAML. CR prior 2nd HCT was no prerequisite. The primary endpoint of the study was disease-free survival (DFS) defined as being alive and free of disease at 1 year post 2nd HCT. Secondary endpoints were relapse, relapse mortality (RM), NRM, overall survival (OS), acute GvHD, chronic GvHD, engraftment, and adverse events. According to the Fleming one-stage design, 50 evaluable patients had to be included. If 16 or more patients were alive and free of disease at 1 year post 2nd SCT, the regimen could be considered as successful for evaluation in further trials. With this decision rule, it can be shown at one-sided α=0.1 that the probability of DFS at 1 year post 2nd HCT is higher than 23% with a power of 90%, when it is at least 40%. This is a first analysis of the study covering the first year after 2nd HCT of each patient. The analysis is based on the full analysis set, which includes all patients, for whom the conditioning regimen TFT and the GvHD prophylaxis regimen CyA, MPA/MMF, ATG-F has started, and for whom allogeneic HCT from an unrelated donor has been performed. Results: Fifty-two patients were registered for the study from 25th March 2014 up to 10th March 2017 from 9 German centres. The full analysis set includes 50 patients (median age 53.5 years). ECOG was median 1. Donors for 1st allo HCT had been related (n=11 (22.0%)) or unrelated (n=39 (78.0%)) (n=48 PBSCT, n=2 bone marrow). Conditioning for 1st HCT was myeloablative in 23 (46.0%) patients. After 1st HCT, the rate of acute GvHD I-IV was 34.0%, and of chronic GvHD was 40.0%. Median time from 1st HCT to relapse was 17.2 months and from relapse after 1st HCT to 2nd HCT 2.5 months. Thirty-six (72%) patients had received induction chemotherapy for relapse prior to 2nd HCT, 11 (22.0%) patients had received azacytidine or decitabine, and 11 (22.0%) had received donor lymphocyte infusions (DLI). Remission status prior to 2nd HCT was complete remission in 16 (32.0%) patients, chemo-refractory relapse in 33 (66.0%), one patient was in partial remission. With regard to the primary endpoint, 23 (46%, 95%-CI (31.8-60.7%) of the patients were alive and free of relapse at 1 year after 2nd SCT. With regard to the secondary endpoints at 1 year, the cumulative incidence of relapse (95%-CI) was 26 (17-42)%, 9/50 patients (18 (10-33)%) died after relapse of AML, NRM was 14/50 patients (28 (18-44)%, cause: infection n=6, infection after aGvHD n=6, PTLD n=2), OS was 54 (39-66)%. Four patients are alive after relapse. aGvHD rate was 54 (42-70)%, aGvHD III-IV 26 (16-42)%, cGvHD 26 (16-42)%, extensive cGvHD 20 (12-35)%, engraftment rate with ANC > 1.0 x 103/µl was 92 (85-100)%, with platelets > 20 x 103/µl was 80 (70-92)%, and with platelets > 100 x 103/µl was 66 (54-81)%. After 1 year, 4 patients had received DLI for prophylaxis, and 5 patients for mixed chimerism as per protocol. Conclusion: Second alloHCT with an ablative double alkylator containing conditioning regimen with Thiotepa, Fludarabine, and Treosulfan is feasible and can result in sustained disease control in patients with AML relapse after a first alloHCT, and therefore seems to be a valid option in this otherwise detrimental setting. Disclosures Finke: Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding. Stelljes:Pfizer: Consultancy, Honoraria, Research Funding; MSD: Consultancy; Novartis: Honoraria; Amgen: Honoraria; JAZZ: Honoraria. Burchert:Novartis: Research Funding; Bayer: Research Funding; AOP Orphan: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria. Schub:Affimed: Research Funding. Kobbe:Celgene: Honoraria, Other: Travel Support, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding.

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