Risk Factors and Outcome of Children with Relapsed/Refractory Acute Leukemia after T-Cell-Rich Haploidentical Hematopoietic Cell Transplantation

Abstract Background: T-cell rich (TCR) HLA-haploidentical SCT (haplo-SCT) is a form of T-cell therapy that has a high degree of efficacy in hematologic malignancies. Previously we reported the safety profile assessing GVHD prophylaxis that was conducted with anti-human thymocyte immunoglobulin (ATG), tacrolimus, methotrexate (MTX) and prednisolone (PSL) in unmanipulated haplo-SCT (Clin Transplant 2010, Transfus Med 2014). We evaluated efficacy and toxicity of TCR haplo-SCT in children with very high risk refractory/relapsed acute leukemia (VHR-R/R AL). Methods: VHR-R/R AL were defined as: relapse after SCT, very early or early relapse, induction failure(2 or more) and relapse of risk factor with MLL rearrangement, Ph+, Mo7 and 5q-. From Aug 2000 to April 2014, consecutive 38 patients (pts) with VHR-R/R AL who underwent TCR-haplo-SCT were included. The median age of pts was 8.2(0.3-19.1) years old. The diagnosis included ALL (n=27), AML (n=8), M/NKL (n=3). The disease status at TCR-haplo-SCT were 18 in CR (positive MRD: 8 pts), 20 in non-CR. HLA disparities were 2/8 in 1pt, 3/8 in 9 pts, 4/8 in 28 pts. Donors included fathers (n=21), mothers (n=14), and siblings (n=3). Thirty one pts received myeloablative conditioning (TBI based: 20 pts, Bu based: 11 pts) and 34 pts of them received ATG (rabbit, thymoglobulin 2.5mg/kg) containing regimen. The GVHD prophylaxis was conducted with tacrolimus, MTX and PSL. Thirty four pts received peripheral blood stem cells and 4 pts received BM. Results: Neutrophil engraftment (defined as >0.5x109/L) was 95% with a median day of 13 (range, 10-15). With a median 1640 days follow-up (range, 320-5510 days) in pts without events, the actuarial 3-year overall survival (OS) and disease-free survival (DFS) were 57% and 39%, respectively. On competing-risk analysis, 1-year cumulative incidences of grade II-IV acute GVHD and chronic GVHD were 71% and 63%, respectively; 3-year cumulative incidences of relapse and non-relapse mortality (NRM) were 40% and 20%. On univariate analysis, 3-year OS in pts with acute GVHD vs. without acute GVHD were 70% vs. 22% (p=.0006), in pts CR vs. non-CR at TCR-SCT were 83% vs. 32% (p=.007), in pts infused CD3 cell doses >=5 x 108/kg vs. <5 x 108/kg were 83% vs. 25% (p=.005), according to age at TCR-SCT <9 vs. >=9 were 79% vs. 34% (.008), respectively. In contrast, the occurrence of acute GVHD had no significant difference in infused CD3 cell doses. Conclusions: These data suggest that TCR haplo-SCT following low-dose ATG containing conditioning combined with our GVHD prophylaxis is well tolerated, facilitates engraftment, and has significant anti-leukemic activity, particularly in pediatric patients with refractory/ relapsed population. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Efficacy and Toxicity of Non-T-Cell Depleted Haploidentical Stem Cell Transplantation in Children with Refractory or Relapsed Acute Leukemia

Blood ◽

10.1182/blood.v118.21.3063.3063 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3063-3063

Author(s):

Atsushi Kikuta ◽

Hideki Sano ◽

Shogo Kobayashi ◽

Mitsuko Akaihata ◽

Masaki Ito

Keyword(s):

T Cell ◽

High Risk ◽

Acute Leukemia ◽

Safety Profile ◽

Cellular Therapy ◽

Nk Cell ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Gvhd Prophylaxis

Abstract Abstract 3063 Background: The efficacy of allogeneic hematopoietic stem celltransplantation(SCT) is primarily attributed to a T/NK- cell-mediatedresponse to HLA disparity between donor and tumor cell. Non-T-cell depleted (non-TCD) HLA-haploidentical SCT (haplo-SCT) is a form of adoptive cellular therapy that has a high degree of efficacy in hematologic malignancies. The major problems of non-TCD haplo-SCT are lethal graft-versus-host disease (GVHD), graft failure (GF) and high-risk of early death. Previously we reported the safety profile from the retrospective study assessing GVHD prophylaxis that was conducted with anti-human thymocyte immunoglobulin(ATG), tacrolimus, methotrexate and prednisolone in non-TCD haplo-SCT (Mochizuki, Kikuta, Clin Transplant, 2010 DOI :10.1111/j.1399–0012.2010.01352.x). We evaluated efficacy and toxicity of non-TCD haplo-SCT in children with very high risk refractory/relapsed acute leukemia (VHR-R/R AL). Methods: VHR-R/R AL was defined by the 1-year survival rate less than 30%. From Aug 2000 to April 2011, consecutive 16 patients (pts) with VHR-R/R AL who underwent non-TCD-haplo-SCT were included. The median age of patients was 7.7(0.5–17.9) years old. The diagnosis included ALL (10), AML (3), M/NKL (3). The disease status at non-TCD-haplo-SCT were 4 in CR2 (MLL rearrangement: 1 pt, Ph positive: 1 pt, after SCT: 2 pts), 12 in non-CR (after SCT: 5 pts, after chemotherapy: 7 pts). HLA disparities were 3/8 in 1 pt, 4/8 in 15 pts. Donors included fathers (9), mothers (5), and siblings (2). Fifteen pts received myeloablative conditioning (TBI based: 11 pts, Bu based: 4 pts) and 1 pt received reduced intensity conditioning, and 12 pts of them received ATG (rabbit, thymoglobulin 2.5mg/kg) containing regimen. The GVHD prophylaxis was conducted with tacrolimus (0.03mg/kg/day, start on day-1), methotrexate (10mg/m2, 7mg/m2, 7mg/m2 on day+1, +3, +6) and prednisolone (1mg/kg/day, day0–29, taper on day30 without GVHD). Thirteen pts received peripheral blood stem cells and 3 pts received bone marrow. Results: All patients achieved engraftment (median 14 days for neutrophils[range: 11–15]). All patients achieved CR in non-remission at non-TCD-haplo-SCT and full donor chimerism by day +30. Acute GVHD grade2–4 and grade 3–4 occurred in 12/16 pts(75%) and 2/16(13%), respectively, all of which were controllable by steroids. Chronic GVHD occurred in 8/13(62%). The treatment-related non-hematologicalcomplications observed within day+100 included: viral reactivations (14 pts [CMV: 8, EBV: 3, VZV; 1, BKV: 1, HHV6: 1]), Candida sepsis(2 pts), Aspergillus(1 pt), Bacterial sepsis(2 pts), hemorrhagic cystitis(2 pts), thrombotic microangiopathy(1 pt), and posterior reversible encephalopathy syndrome(1 pt). Non-relapsed mortality occurred in 3 pts and the causes of death were CMV-peumonia(1 pt) and EBV-lymphoproliferative disease(2 pts) which occurred day+48, day+71 and day+439, respectively. Relapse occurred in 2 pts. With the median follow-up of 12(6–133) months, 1-year and 2-year event free survival (EFS) were 73% and 61%. Conclusions: These data suggest that non-TCD haplo-SCT combined with our GVHD prophylaxis is well tolerated, facilitate engraftment, and has significant anti-tumor activity, particularly in pediatric patients with non-remission acute leukemia. The safety profile is acceptable in this refractory/ relapsed population. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Overall and Disease-Specific Outcomes Following T-Cell Replete Haploidentical Transplants Using Post-Transplant Cyclophosphamide: An Analysis Of 115 Patients Transplanted At a Single Center

Blood ◽

10.1182/blood.v122.21.3337.3337 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3337-3337

Author(s):

Asad Bashey ◽

Xu Zhang ◽

Zaamin Hussain ◽

Stacey Brown ◽

Lawrence E. Morris ◽

...

Keyword(s):

T Cell ◽

Graft Rejection ◽

Acute Gvhd ◽

Disease Risk ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Disease Free Survival ◽

Hematologic Malignancies ◽

Effective Control ◽

Post Transplant

Abstract Many patients with hematologic malignancies who may benefit from the curative potential of allogeneic hematopoietic cell transplantation (allo-HCT) will lack a conventional matched sibling (MRD) or matched unrelated (MUD) donor. An HLA-haploidentical related donor is available for nearly all such patients. Attempts to use haploidentical donors that employ stringent ex-vivo T-cell depletion to abrogate GVHD are associated with poor immune reconstitution and high rates of graft rejection. In contrast, the recent use of T-cell replete grafts with post-transplant cyclophosphamide (haplo-ptCy) has resulted in effective control of alloreactivity with low rates of post-transplant infection, graft-rejection and non-relapse mortality using both non-ablative and ablative regimens (Luznik at al BBMT 2008, Solomon et al BBMT 2012.). We recently demonstrated similar outcomes for 53 haplo-PtCy to contemporaneous MRD and MUD transplants performed at our enter (Bashey et al JCO 2013). However there are limited data with respect to the outcome of specific hematologic malignancies using haplo-ptCy. For this study all consecutive patients who underwent haplo-ptCy as a first allogeneic transplant at our center between Oct 2005 and May 2013 (n=115) were included [median age 50 (20-74); M 57%, F 43%; diagnosis- AML(38), ALL(20), CLL(13), NHL(13) HL(10), CML+MPS (12), MDS (7) others (2); graft-BM(58%),PBSC(42%); prior autotranplant(18%); CIBMTR disease risk score high(35%), intermediate(32%) low(33%). Sorror Comorbidity Index-median =1(0-5)]. Preparative regimens used included non-myeloablative [fludarabine 30 mg/m2/d d -6 to -2; TBI 200cGy d-1, Cy 14.5 mg/kg/d on d-6,-5 and 50mg/kg/d on d+3,+4, n=73 ] and myeloablative [regimen 1- same as non-ablative except busulfan 110-130 mg/m2 /d i.v. on d-7 to-3 instead of TBI n=21; regimen 2- fludarabine 30 mg/m2/d d -7 to -5, TBI 150cGy bid x 8 doses (total dose =1200cGy) and Cy 50mg/kg/d d+3,+4 n=21]. Patient characteristics and outcome data were collected prospectively and obtained from our comprehensive database. Survival and disease-free survival (DFS) were estimated using the Kaplan-Meier method. Cumulative incidence of non-relapse mortality (NRM) was calculated using relapse as a competing risk. GVHD was assessed and documented prospectively by a dedicated GVHD nurse. Median CD34+ and CD3+cell doses infused were 4.21 x 10e6/kg (0.84-8.13) and 5.81 x 10e7/kg (1.4-59.5). median time to ANC > 500/mm3 and platelets > 20,000/mm3 were 16 and 26 d. Median % donor chimerism on d 30 were 100% and 100% for PB CD3+ and CD33+ cells respectively. With a median follow-up for living patients of 20 months, the 12 m and 24 m cumulative incidences (CI) of NRM were 10% and 18% and of relapse/progression were 25% and 25% respectively (Fig.1). CI of acute GVHD gd II-IV and gd III-IV at 6 m were 34% and 13% respectively, and of extensive and severe chronic GVHD at 12 m were 40% and 9% respectively. Estimated 12m and 24m probabilities of survival were 73% and 56% and of DFS were 65% and 57% respectively. On a Cox multivariate analysis assessing patient, disease and transplant related covariates, high risk CIBMTR disease score (HR 1.88, p=0.043) and acute GVHD gd 3-4 HR=2.54, p=0.0145) were the only factors significantly associated with survival. For the most frequently treated diagnoses - AML, ALL and mature lymphoid malignancies (CLL, NHL, HL) - the respective estimated 24 m probabilities of DFS were 61%, 58% and 50% respectively (Fig.2). These data demonstrate that haplo-ptCy transplants represent a safe and effective alternative for most patients who may benefit from allo-HCT but lack a conventional donor. They should be offered as standard of care in such patients. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

HLA-Identical Sibling-Matched, CD34+ Selected, T Cell Depleted Peripheral Blood Stem Cells Following Myeloablative Conditioning for First or Second Remission Acute Myeloid Leukemia (AML): Results of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 0303.

Blood ◽

10.1182/blood.v114.22.655.655 ◽

2009 ◽

Vol 114 (22) ◽

pp. 655-655 ◽

Cited By ~ 1

Author(s):

Steven M. Devine ◽

Robert J Soiffer ◽

Marcelo C. Pasquini ◽

Shelly Carter ◽

Parameswaran N Hari ◽

...

Keyword(s):

T Cell ◽

Hematopoietic Cell Transplantation ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Unrelated Donor ◽

Post Transplant ◽

Gvhd Prophylaxis

Abstract Abstract 655 Allogeneic hematopoietic cell transplantation (HCT) is the most effective means to prevent relapse in patients (pts) with AML in complete remission (CR). However, quality of life and overall survival (OS) are often affected by both acute and chronic graft versus host disease (GVHD). GVHD is most effectively prevented by ex vivo T cell depletion (TCD) of the allograft, but has been limited in its use by logistical difficulties, lack of an FDA-approved method, and concerns regarding potential risk of graft rejection, post transplant infections, and leukemic relapse. Most reported TCD studies represent single centers, multiple disease types and processing methods with varying degrees of TCD, all of which affect outcome. Therefore we designed a trial using a single processing method providing extensive TCD that did not require post transplant GVHD prophylaxis involving adult pts with AML in first or second CR. We hypothesized that the undesired side effects of TCD HCT would be reduced if combined with a conditioning regimen that was highly immunosuppressive and anti-leukemic. The primary objective was to achieve a disease-free survival (DFS) rate at 6 months (mos) post transplant that exceeded 75%. Secondary objectives included assessments of engraftment, transplant related mortality (TRM), GVHD, relapse, and performance of a single TCD method (CD34+ cell selection using the Miltenyi CliniMACS device) at participating centers. From 10/2005 to 12/2008, 47 pts were enrolled and 44 transplanted at 8 different centers. Median age was 48.5 years (range 21-59) with 28 female and 16 male pts. Of 37 AML CR1 pts, 49% had an unfavorable cytogenetic or molecular risk profile. The conditioning regimen consisted of hyperfractionated total body irradiation (1375cGy in 11 fractions) with partial lung shielding, thiotepa (10mg/kg), cyclophosphamide (120mg/kg), and rabbit antithymocyte globulin (2.5mg/kg). The donors, all HLA-identical siblings, were given G-CSF for mobilization and scheduled to undergo at least 2 leukapheresis procedures to ensure a graft with a high CD34+ cell content. All allografts were CD34-enriched and were targeted to contain ≥ 5×10e6 CD34+ cells/kg and < 1.0×10e5 CD3+ cells/kg. The median CD34+ and CD3+ doses achieved were 8.1 × 10e6/kg (range 2.4-46.2) and 0.07 × 10e5/kg (range 0.01-0.85), respectively. The majority (81%) of pts received the targeted CD34+ cell dose and no pt received > 1.0×10e5 CD3+ cells/kg. No pharmacological GVHD prophylaxis was given post transplant. There were no significant toxicities related to infusion of the CD34 enriched allografts. The most common grade 3-5 regimen-related toxicities included grades 3 or 4 mucositis (39%) and grades 3-5 pulmonary abnormalities (11%). Only 1 pt experienced hepatic veno-occlusive disease. All pts engrafted rapidly with a median time to neutrophil recovery (ANC > 500/ul) of 11 days (range 9-19). There was 1 secondary graft failure. The assessed outcomes are shown below.Estimate (95% Confidence Interval)Outcome100 Days6 Months12 MonthsAcute GVHD II-IV20.5% (8.7 – 23.3%)Acute GVHD III-IV4.5% (0 – 10.6%)Chronic GVHD17.7% (5.8-29.6%)Extensive Chronic GVHD7.6% (0-15.7%)TRM17.8% (5.8-29.8%)Overall Relapse18.2% (5.9-30.5%)Relapse 1st CR9.6% (0- 19.8%%)Relapse 2nd CR64.3% (27.5-100%)DFS81.3% (66.1-90.2%)64.0% (46.5-77.1%)DFS 1st CR89.2% (73.7-95.8%)72.1% (53.0-84.6%)OS74.3% (57.3-85.4%) The absolute peripheral CD4+ cell count remained on average below 200/ul until day +365. Donor cell chimerism increased in the CD3+ cell compartment through day +365. There were 14 deaths. The most common causes of death were relapse (N=5) and pulmonary toxicity (N=4). The median follow-up of survivors is 489 days (range 96-776). There was no difference in OS or DFS for pts above or below the median age of 48.5 years. We conclude that TCD HCT following myeloablative chemoradiotherapy can be performed in a multi-center setting using a single TCD method without additional post transplant prophylaxis with excellent DFS and OS, consistent engraftment, low TRM, and low incidence of relapse even in pts with unfavorable risk AML in CR1. The low incidences of acute and chronic GVHD in the absence of post transplant prophylaxis were particularly encouraging. A follow-up study of TCD HCT in AML recipients of unrelated donor allografts is being planned by the BMT CTN Disclosures: No relevant conflicts of interest to declare.

Download Full-text

T-cell subpopulations identified by monoclonal antibodies after human marrow transplantation. I. Helper-inducer and cytotoxic-suppressor subsets

Blood ◽

10.1182/blood.v59.6.1292.1292 ◽

1982 ◽

Vol 59 (6) ◽

pp. 1292-1298 ◽

Cited By ~ 120

Author(s):

K Atkinson ◽

JA Hansen ◽

R Storb ◽

S Goehle ◽

G Goldstein ◽

...

Keyword(s):

Monoclonal Antibodies ◽

T Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Absolute Number ◽

Cell Sorter ◽

Graft Versus Host ◽

Significant Difference ◽

Cell Subpopulations ◽

T Cell Subpopulations

Abstract Peripheral blood helper-inducer and cytotoxic-suppressor T-cell subpopulations in patients receiving marrow transplants for the treatment of acute leukemia or severe aplastic anemia were quantitated on the fluorescence-activated cell sorter (FACS) using the monoclonal antibodies OKT4 and OKT8, respectively. The relative (percent) and absolute number of OKT4+ cells were severely and persistently depleted for up to 2.7 yr posttransplant. In contrast, the percent and absolute number of OKT8+ cells began to recover within the first 60 days of transplant and subsequently remained at normal or high levels for periods of up to 7.3 yr. There was no significant difference in percent or absolute numbers of OKT8+ cells for patients with or without acute graft-versus-host disease (GVHD). The reversal of the normal OKT4:OKT8 ratio (2:1) occurred regardless of whether the recipient was given an allogeneic, syngeneic, or autologous transplant and regardless of whether or not acute or chronic GVHD developed. The reversed ratio was due in the first 3 mo posttransplant to low numbers of OKT4+ cells and later to a combination of low numbers of OKT4+ and high numbers of OKT8+ cells. Normalization and then an increase in the number of OKT8+ cells correlated with increasing time posttransplant and not with resolution of acute GVHD.

Download Full-text

Unrelated Cord Blood Transplantation Using Myeloablative Regimen for Acute Leukemia Patients Aged between 50 and 55 Years: Single Institutional Retrospective Comparison with Patients Less Than 50 Years of Age.

Blood ◽

10.1182/blood.v110.11.2013.2013 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2013-2013

Author(s):

Takaaki Konuma ◽

Satoshi Takahashi ◽

Jun Ooi ◽

Akira Tomonari ◽

Nobuhiro Tsukada ◽

...

Keyword(s):

Acute Leukemia ◽

Cord Blood ◽

Older Patients ◽

Acute Gvhd ◽

Cord Blood Transplantation ◽

Chronic Gvhd ◽

Age Groups ◽

Younger Patients ◽

Cell Dose ◽

Significant Difference

Abstract Background: Increasing age has been well-known as an obvious risk factor for graft-versus-host disease (GVHD) and transplant-related mortality (TRM) resulting negative impact on allogeneic transplantation including cord blood transplant (CBT). The incidence of sever GVHD after CBT, on the other hand, is lower than that after transplants using graft from adult cells, so we have expected the better results of CBT in older patients. Objectives and Methods: This study aimed to evaluate safety and efficacy of CBT using myeloablative regimen for older patients with acute leukemia. Patients and Methods: We retrospectively compared outcomes of older patients with acute leukemia with younger adults in our institute. Nineteen elderly patients (median age 52, range 50–55) and 81 young patients (median 49, range 16–49) received myeloablative conditioning regimen including 12 Gy of total body irradiation. GVHD prophylaxis comprised cyclosporine with (N=96) or without (N=4) methotrexate. Results: Comparisons of characteristics in the 2 age groups showed similar distributions for weight, gender ratio, diagnosis [de novo acute myeloid leukemia (AML), myelodysplastic syndrome related secondary AML, or acute lymphoblastic leukemia], disease status at transplantation, total nucleated cell dose and CD34+ cell dose in the graft before cryopreservation and proportions of HLA and sex compatibility between donors and recipients. The median period of follow-up for survivors after CBT was 730 days for older group and 1331 days for younger group, respectively. Grade II to IV acute GVHD occurred in 10 of 17 evaluable older patients and 49 of 75 evaluable younger patients (P = 0.61), while no older patients, but 6 younger patients developed grade III to IV acute GVHD. Extensive-type chronic GVHD occurred in 4 of 15 evaluable older patients and 18 of 69 evaluable younger patients (P = 0.96), respectively. The cumulative incidence of TRM at 100 days was 5% versus 6% (P = 0.70), and of relapse at 3 years was 29% versus 20% (P = 0.33) and the estimated disease-free survival at 3 years was 67% and 71% (P = 0.53) for older or younger patients, respectively. There was no significant difference in GVHD, TRM, relapse, and DFS between 2 age groups. Conclusion: The use of cord blood as a stem cell source might contribute to be decreased in the incidence of acute and chronic GVHD resulting in decreased TRM in older patients. Our results suggest that myeloablative CBT might be as safe and effective in patients with acute leukemia aged between 50 and 55 years as in younger patients.

Download Full-text

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

Download Full-text

Double-Unit Cord Blood Transplantation (DCBT) for Acute Leukemia: High Disease-Free Survival in Adults and Children with Comparable Survival in European and Minority Patients

Blood ◽

10.1182/blood.v118.21.3080.3080 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3080-3080

Author(s):

Juliet N Barker ◽

Doris M Ponce ◽

Anne Marie R Gonzales ◽

Marissa N Lubin ◽

Hugo Castro-Malaspina ◽

...

Keyword(s):

High Risk ◽

Acute Leukemia ◽

Conflicts Of Interest ◽

Cord Blood Transplantation ◽

Univariate Analysis ◽

Disease Free Survival ◽

European Ancestry ◽

High Dose ◽

Free Survival ◽

Disease Free

Abstract Abstract 3080 As compared to single-unit CBT, DCBT may improve engraftment and protect against relapse. Therefore, we have adopted DCBT for both children and adults with acute leukemia, myelodysplasia (MDS), and myeloproliferative diseases (MPD). However, determinants of disease-free survival (DFS) have yet to be fully established. Furthermore, whether DFS after DCBT is comparable in patients of European and non-European ancestry is of special interest. Therefore, we analyzed the DFS of 75 DCBT recipients with acute leukemia in morphologic remission or aplasia (n = 69), and MDS/MPD with ≤ 5% blasts (n = 6) transplanted from 10/2005-4/2011. Nearly all patients had high-risk disease. Children 0–15 years (n = 23) had the following characteristics: median age 9 years (range 0.9–15); median weight 37 kg (range 7–72); 30% European; and 26% CMV sero-positive. Diagnoses were 43% AML (or biphenotypic), 52% ALL, and 4% MDS/MPD, and all received high-dose conditioning. The children received grafts with a median infused TNC × 107/kg of 3.3 (larger unit) and 2.6 (smaller unit), and 2% of units were 6/6 HLA-A, -B antigen, -DRB1 allele matched, 63% 5/6, and 35% 4/6. Adults ≥ 16 years (n = 52) had the following characteristics: median age 41 years (range 16–69); median weight 69 kg (range 47–105); 48% European; 69% CMV sero-positive; and diagnoses were 63% AML (or biphenotypic), 27% ALL, and 10% MDS/MPD. Fifty percent received high-dose and 50% reduced intensity conditioning. Their units had a median infused TNC/kg of 2.7 and 1.9, and 3% were 6/6 HLA-matched, 47% 5/6, and 50% 4/6. All patients (pediatric and adult) received calcineurin-inhibitor/ mycophenolate mofetil immunosuppression, and none received anti-thymocyte globulin. Sustained donor neutrophil engraftment was seen in 91% of children and 94% of adults at medians of 20 and 26 days, respectively. The incidence of grade II-IV acute GVHD by day 180 was 44% in children and 58% in adults. Day 100 transplant-related mortality (TRM) was 9% in children and 19% in adults. The 2-year relapse incidence was 9% in children and 6% in adults. With a median follow-up of survivors of 26 months (range 4–70), 2-year Kaplan-Meier estimate of DFS was 78% in children and 64% in adults (Figure). Differences in survival by age did not reach significance. Univariate analysis of variables potentially influencing 2-year DFS (with log rank estimates of significance) in all patients is shown in the Table. There were no differences in 2-year DFS according to ancestry, remission status, and conditioning intensity. There was also no difference in 2-year DFS according to engrafting unit-recipient HLA-match (4-6/6 or 10 allele), or engrafting unit infused TNC dose/kg. However, patients who were CMV seronegative had a higher 2-year DFS (85% vs 55%, p = 0.018). Multivariate analysis revealed recipient CMV serostatus was a predictor of DFS independent of patient age, and its effect was mediated by an influence on TRM. We have previously shown that DCBT extends transplant access to minority patients. We now demonstrate that DCBT can achieve high and comparable DFS in both European and non-European pediatric and adult patients with acute leukemia and MDS/MPD. While these are very encouraging results further investigation in racial/ethnic sub-groups is needed. Nonetheless, our findings support DCBT as an immediate alternative therapy for high-risk acute leukemia in patients without suitable unrelated volunteer donors, especially given the very low incidence of relapse. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

CD28-Directed T Cell Costimulation Blockade with Abatacept to Prevent GvHD During High-Risk Unrelated HSCT: A First-in-Disease Feasibility Trial,

Blood ◽

10.1182/blood.v118.21.4078.4078 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4078-4078

Author(s):

Leslie S. Kean ◽

Amelia Langston ◽

Muna Qayad ◽

H. Jean Khoury ◽

Divya Tiwari ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Hematologic Malignancies ◽

Feasibility Trial ◽

Effector Memory ◽

Unrelated Donor ◽

Gvhd Prophylaxis ◽

The Mean

Abstract Abstract 4078 Background: Acute GvHD remains the major cause of complications and death following unrelated-donor HSCT. In a non-human primate model, we have previously shown that in vivo costimulatory blockade of donor T-cells could provide effective protection against GVHD. To begin to explore its clinical utility, we are conducting a trial (Clinical Trials.Org # NCT01012492) to determine the feasibility of combining abatacept (CTLA4-Ig) with cyclosporine and methotrexate as acute GVHD prophylaxis for patients undergoing unrelated marrow and peripheral blood stem cell transplants for hematologic malignancies. Methods: Patients older than 12 with advanced hematologic malignancies, conditioned with either TBI/Cytoxan, Busulfan/Cytoxan or Fludarabine/Melphalan are eligible. Abatacept is administered IV on days −1, +5, +14, and +28 at 10 mg/kg in addition to standard GvHD prophylaxis consisting of cyclosporine (day −2 to day 100), and methotrexate (15 mg/m2 on day +1 and 10 mg/m2 on days +3, 6 and 11). Patients are then followed for clinical outcomes and immunologic reconstitution through day +365. Results: 9 patients (planned enrollment = 11 patients) have thus far been enrolled on the study of which 5 are evaluable for engraftment, toxicity and acute GvHD. The other four patients consist of 2 who are currently receiving abatacept, 1 who was discovered to have an ongoing viral infection at the start of the first abatacept infusion so was removed from the treatment regimen, and 1 who is awaiting transplant. The median age for the 5 evaluable patients is 47 years (17–74 years). 3 patients had AML and 2 had ALL. Patients were conditioned with Bu/Cy (n=1), TBI/Cy (n=2) and Flu/Melphalan (n=2). 4 donor-recipient pairs were allele matched at 9 of 10 loci (A, B, C, DRB1 and DQB1), while 1 was fully matched. Four of the 5 patients are currently alive and in remission and 1 relapsed at day +98 (and died on day +121 with refractory AML). The four other patients are surviving without relapse with a follow-up of 155–313 days. All 5 patients received the 4 scheduled abatacept doses. No infusional side effects were noted. All patients achieved neutrophil engraftment (median day +20 (11–47). 4 of 5 patients have achieved platelet engraftment (median day +27 (14–35). Donor engraftment (100% CD33 and 99–100% CD3 at Day +30) occurred in all cases. All patients have demonstrated rapid lymphocyte engraftment, with the mean ALC reconstituting to >500 cells/μL by day +21 post-transplant. At day +100, the mean CD3+ count was 673 +/− 251 cells/μL. Both CD8+ and CD4+ T cells reconstituted by day 100, with the mean CD8+ count = 384 +/− 148 cells/μL and the mean CD4+ count = 229 +/− 119 cells/μL. T cell reconstitution was accompanied by a shift away from naïve (Tn, CCR7+/CD45RA+) toward a CCR7-/CD45RA- effector memory (Tem)-predominant phenotype. Thus, the average proportion of CD4+ Tem cells in the recipient increased from 22 +/− 6% pre-transplant to 46 +/− 7% at day +100 with a concomitant loss of CD4+ Tn cells. Likewise, the proportion of CD8+ Tem also significantly increased, from an average of 15 +/− 4% pre-transplant to 32 +/− 7% at day +100, also with a reciprocal decrease in CD8+ Tn cells. One patient developed steroid responsive grade 3 acute GVHD involving the skin and the liver, followed by steroid responsive liver chronic GvHD. This patient is currently weaning corticosteroids. Another patient developed steroid responsive late-onset (day +217) acute GVHD (liver and GI) during cyclosporine weaning, which was also steroid responsive, and is also currently weaning corticosteroids. No other systemic acute or chronic GvHD has occurred. No unexpected complications or life-threatening infections were observed. 3 patients have experienced 5 episodes of CMV reactivation, all responsive to antiviral therapy. One patient developed polyclonal EBV-related PTLD (plasmacytic hyperplasia) in the absence of EBV viremia, which regressed without intervention. No other EBV-related disease has occurred. Conclusions: These preliminary data suggest that abatacept can be safely added to cyclosporine and methotrexate for GVHD prophylaxis in recipients of hematopoietic grafts from unrelated donors, with encouraging rates of acute GVHD. As such, they support the conduct of a larger, randomized phase 2 study. Disclosures: Off Label Use: Abatacept: It is an immunosuppressive agent that targets the CD28/B7 T cell costimulation pathway. It is approved for use in Rheumatoid arthritis.

Download Full-text

HLA-Mismatch Is Associated With Worse Outcomes After Unrelated Donor Reduced Intensity Conditioning Hematopoietic Cell Transplantation: A Cibmtr Analysis

Blood ◽

10.1182/blood.v122.21.547.547 ◽

2013 ◽

Vol 122 (21) ◽

pp. 547-547 ◽

Cited By ~ 2

Author(s):

John Koreth ◽

Kwang Woo Ahn ◽

Joseph Pidala ◽

James L. Gajewski ◽

Hailin Wang ◽

...

Keyword(s):

T Cell ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Cell Depletion ◽

Unrelated Donor ◽

T Cell Depletion ◽

Gvhd Prophylaxis ◽

Conditioning Intensity

Abstract In myeloablative unrelated donor allogeneic hematopoietic cell transplantation (HCT) a 1-locus HLA-mismatch (-A, -B, -C, -DRB1) is associated with lower survival compared to fully matched pairs. However data in reduced-intensity and non-myeloablative conditioning (together called RIC) HCT are limited. We analyzed adult AML/ALL/CML/MDS recipients of first 8/8 HLA-matched or 1-locus mismatched unrelated donor (MUD, MMUD) RIC HCT performed in the period 1999-2011 and registered in the CIBMTR. HLA-A, -B, -C and -DRB1 loci were typed in all pairs at high resolution; -DQB1 and -DPB1 loci could not be evaluated in all pairs. Transplants involving ex-vivo T-cell depletion, CD34+ selection, or post-transplant cyclophosphamide were excluded. Overall survival (OS) was the primary outcome. Secondary outcomes included non-relapse mortality (NRM), relapse, disease-free survival (DFS) and acute and chronic GVHD. Individual locus mismatch was also assessed. Apart from HLA matching, variables related to patient (age, race, sex, KPS, diagnosis, disease-risk), donor (age, parity), both (sex match/ABO match/CMV match) treatment (conditioning intensity, TBI use, in-vivo T-cell depletion (ATG), graft source (PB, BM) and GVHD prophylaxis (CyA-, Tac-based)) were considered. 2588 RIC HCT (8/8 MUD: 2025; 7/8 MMUD: 563) from 144 centers and 12 countries were analyzed. Median follow up in 8/8 MUD and 7/8 MMUD was 38 and 48 months respectively. Diagnoses were AML (65%), ALL (8%), CML (7%), MDS (20%). Conditioning intensity was RIC (79%), NMA (21%). 58% received in-vivo T-cell depletion. Graft source was PBSC (85%), BM (15%). GVHD prophylaxis was Tac-based (70%), CyA-based (27%). Mismatches involved HLA-A (188), -B (81), -C (219), and -DRB1 (75); with -DPB1 and -DQB1 typing available in 1382 and 2502 cases respectively. Compared to 8/8 MUD, 7/8 MMUD recipients were more likely to be younger and ethnic minorities and to have older and parous donors. In univariate analyses DQB1- and -DPB1 mismatch was not associated with worse OS, DFS, or NRM and was not further evaluated. There was a trend toward more grade II-IV acute GVHD in -DPB1 double (p=0.02) but not single mismatches. In multivariate models 7/8 MMUD RIC HCT had worse grade II-IV and III-IV acute GVHD, NRM, DFS and OS, but not relapse or chronic GVHD (Table). No significant interactions were identified between degree of HLA matching and other clinical variables. Adjusted 1- and 3-year NRM for 8/8 MUD vs. 7/8 MMUD was 20.4% vs. 28.9% (p<0.0001) and 29.2% vs. 38.1% (p<0.0007) respectively. Adjusted 1- and 3-year OS was 54.7% vs. 48.8% (p=0.01) and 37.4% vs. 30.9% (p=0.005) respectively (Figure). There was no difference between allele and antigen mismatches. HLA-A, -B, -C, and -DRB1 locus mismatches were each associated with 1 or more impaired outcomes (acute GVHD, NRM, DFS, and/or OS). Table 1 7/8 vs. 8/8 HLA HR (95% CI) p-value Acute GVHD II-IV 1.29 (1.09-1.53) 0.003 Acute GVHD III-IV 1.69 (1.00-3.36) 0.05 Chronic GVHD 1.11 (0.96-1.28) 0.15 Relapse 1.01 (0.87-1.17) 0.92 NRM 1.52 (1.29-1.79) <0.0001 DFS 1.20 (1.07-1.34) 0.0015 OS 1.25 (1.11-1.40) 0.0001 Compared to 8/8 MUD, both 7/8 allele and antigen MMUD RIC HCT have greater treatment toxicity and worse survival, of a magnitude similar to that seen in myeloablative transplantation. An isolated mismatch at HLA-A, -B, -C, or -DRB1 was associated with 1 or more adverse outcomes. In unrelated donor RIC HCT, matching for all alleles of HLA-A, -B, -C and -DRB1 loci results in superior outcomes. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Comparison Between Related T-Cell Depleted HLA-Haploidentical Stem Cell Transplantation (TCD-Haplo) and Umbilical Cord Blood Transplantation (UCBT) in Pediatric Patients with Acute Leukemia, a Eurocord, PDWP-EBMT Study

Blood ◽

10.1182/blood.v124.21.1215.1215 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1215-1215

Author(s):

Franco Locatelli ◽

Myriam Labopin ◽

Gerard Michel ◽

Rupert Handgretinger ◽

Cristina Diaz de Heredia ◽

...

Keyword(s):

Multivariate Analysis ◽

Acute Leukemia ◽

Advanced Disease ◽

Cord Blood Transplantation ◽

Chronic Gvhd ◽

Univariate Analysis ◽

Conditioning Regimen ◽

Disease Status ◽

Gvhd Prophylaxis ◽

Risk Of Relapse

Abstract Both TCD-Haplo and UCBT are used for treating children with either acute lymphoblastic (ALL) or myeloid (AML) leukemia in need of an allograft and lacking a suitable donor. Although both these types of HSCT have been shown to be effective in curing children with acute leukemia, to date, no study has compared the outcomes of these two types of transplant. We performed a retrospective registry-based study on children (less than 18 years) with either ALL or AML, receiving, after a myeloablative conditioning regimen, a TCD-Haplo (CD34+ cell positive selection, CD3+ negative or TCR alpha/beta+ cell depletion) or single unit UCBT. Patients given pharmacological graft-versus-host disease (GVHD) prophylaxis after graft infusion in haplo HSCT were excluded. Transplants were performed from 2001 to 2012 in EBMT centers; 1067 patients received single UCBT and 266 TCD-Haplo for AML (n=478) or ALL (n=855). Median follow up was 28 (range 1-150) and 20 (range 1-152) months for UCBT and TCD-Haplo, respectively. Compared to TCD-Haplo, UCBT recipients were younger (median age 5.96 years vs 9.6 years, p=<0.0001), were transplanted more frequently in CR1 (42% vs 24%, p=<0.001), less frequently in advanced disease (10% vs 21%, p=<0.001) and had more often negative cytomegalovirus (CMV) serology (45% vs 31%, p=<0.001). Conditioning regimen was mainly total body irradiation (TBI)-based, 56% versus 50% for TCD-Haplo and UCBT, respectively. For UCBT, patients CSA+steroids was the most commonly used (72%) GVHD prophylaxis. A higher proportion of patients transplanted with TCD-Haplo received ATG in the conditioning regimen (90% vs 74%, p=<0.001). Acute GVHD (grade II-IV) incidence was 16% and 28% (p<0.001) while that of chronic GVHD was 14% and 16%, (p=0.40) for TCD-Haplo and UCBT respectively. Since diagnosis was the most important factor influencing outcome, the analysis was performed separately for patients with ALL and AML. For ALL (n=855) in univariate analysis, the 2-year probability of leukemia-free survival (LFS) was 35% and 43% (p=0.08), for TCD-Haplo and UCBT, respectively. The cumulative incidence (CI) of non-relapse mortality (NRM) was 28% and 29% (p=0.57), and relapse incidence (RI) was 36% and 28% (p=0.01) for TCD-Haplo and UCBT, respectively. According to disease status, for patients in CR1 (n=300), 2-year RI was 21% versus 20%, p=0.75; NRM 30% versus 24%, p=0.59; and 2- year LFS 49% versus 56%, p=0.87; for TCD-Haplo and UCBT, respectively. For patients in CR2 (n=478), 2-year RI was 34% versus 29%, p=0.75; NRM 28% versus 32%, p=0.29; and 2- year LFS 38% versus 39%, p=0.63, for TCD-Haplo and UCBT, respectively. For patients in advanced disease (n=77), 2-year LFS was 5% versus 8%, p=0.08 for TCD-Haplo and UCBT, respectively. For patients with AML (n=478), 2-year probability of LFS was 21% and 58% (p=<0.0001), for TCD-Haplo and UCBT, respectively. CI of NRM was 43% and 19% (p=<0.001), and RI was 36% and 23% (p=0.01) for TCD-Haplo and UCBT, respectively. According to disease status, for patients in CR1 (n=207), 2-year RI was 31% versus 14%, p=0.06; NRM 45% versus 16%, p=0.002; and 2-year LFS 24% versus 69%, p=<0.001; for TCD-Haplo and UCBT, respectively. For patients in CR2 (n=180), 2-year RI was 28% versus 24%, p=0.49; NRM 44% versus 21%, p=0.004; and 2- year LFS 28% versus 55%, p=0.0005, for TCD-Haplo and UCBT, respectively. For patients in advanced disease status (n=91), 2-year LFS was 10% versus 22%, p=0.44 for TCD-Haplo and UCBT, respectively. In multivariate analysis adjusted for differences between the 2 groups, for patients with ALL, no statistically significant differences were observed according to the graft source. Disease status was the only factor associated with better LFS (HR 4.84, p<0.0001). TCD-Haplo was associated with greater risk of RI (HR 1.58, p=0.01). For AML, in multivariate analysis, TCD-Haplo was associated with greater risk of relapse (HR 1.67, p=0.05) and of NRM (HR= 1.94; p=<0.001), and worse LFS (HR 1.94, p=<0.001) when compared to UCBT. Advanced disease at transplantation (HR 2.89, p=<0.001) was the other factor associated with LFS and RI. This retrospective analysis demonstrates that children with ALL have comparable probability of LFS after either UCBT or TCD-Haplo. By contrast, in children with AML, UCBT is associated with lower risk of relapse and NRM than TCD-Haplo, this translating into better LFS. These results may help guide physician choices for transplanting children with acute leukemia. Disclosures No relevant conflicts of interest to declare.

Download Full-text