Outpatient Haploidentical Peripheral Blood Stem-Cell Transplantation with Post-Transplant Cyclophosphamide in Children and Adolescents

Abstract Patients with high-risk hematological malignancies have a poor prognosis without a hematopoietic stem cell transplant. An HLA- haploidentical donor is available in 95% of the cases, and post-transplant cyclophosphamide permits the use of T-cell replete grafts in settings were ex-vivo manipulation is not available. The experience with HLA-haploidentical HSCT with PBSC and post-tranplant Cy in the pediatric and adolescent population is limited; we report the following experience. We retrospectively collected data on 25 patients (0 to 21 years old) with hematological malignancies, who underwent ambulatory haploidentical HSCT with post-transplant Cy from November 2011 to November 2014. The different conditioning regimens are described in Table 1. All patients received high-dose Cy(50mg/kg) on days +3 and +4. Cyclosporine A (CYA; 6mg/kg/d per os) and mycophenolate mofetil (MMF; 15mg/kg two times daily per os) were started on day +5. MMF was discontinued on day +35 and tapering of cyclosporin started day +90 in the absence of GVHD. All patients received anti-microbial prophylaxis for bacteria, fungal, herpes infection and Pneumocystis jiroveci according to institutional practices. First chimerism was performed at day +30, and second chimerism at day +100. Primary graft failure was defined when neutrophil counts did not exceed 0.5 x 109/L by day +30. Acute and chronic GVHD were graded according to NIH criteria. Patient, donor and stem-cell harvest characteristics are described in Table 1. All patients had high risk hematological malignancies. There were 5 patients who underwent their first transplant on 1st CR, 4 with ALL with high risk cytogenetics and 1 with AML. All other patients were defined as high risk because they were refractory/relapsed. Twenty-three patients (92%) had neutrophil engraftment after a median 17 (7-24) days. Platelet engraftment was observed in 20 (80%) patients after a median of 14.5 (11-23) days, 3 (12%) patients did not have platelet counts below 20,000/mcL. One patient was catalogued as a primary failure for not achieving neutrophil and platelet engraftment by day +30. One patient died before engraftment at day +10 of septic shock. Four patients (16%) died before day +30. The only patient that did not have a complete chimerism, had a diagnosis of AML and 30% of donor cells by day +30, by day +45 relapse of disease was documented. After a median follow-up of 157 days, 13 patients (52%) remain alive, with an estimated 1-year OS of 52% (95%CI: 30.4 - 65.6%).Nine patients (36%) died of complications (mainly infectious) not related to relapse at a median time of 66 days (10-579 days) from stem cell infusion. Nine patients (36%) relapsed in a median time of 105 days (45-288 days); three of those patients died at days +150, +113 and + 370 from transplant. Estimated 1 year event-free survival is 40.2% (95%CI: 41.3 - 75.8%) (Figures 1 and 2). Patients transplanted on 1st CR had a median follow-up of 664 days with an OS and EFS of 80% (4 patients), which was statistically different from the rest of the population (p=0.03) (Figure 3). Among those who engrafted (n=21), 9 cases (42.9%) had grade 2-4 acute GVHD and 4 cases (19%) of grade 3-4 acute GVHD. Three patients (14.3%) developed chronic GVHD, two had mild skin or liver cGVHD. One patient had severe (NIH stage 3) skin cGVHD, she was alive and with a grade 2 cGVHD until last follow up at day +893. Outpatient procedure, HLA-haploidentical HSCT including PBSC as a stem cell source, and post-transplant T-cell in vivo depletion using high-dose cyclophosphamide is feasible in children and adolescents, with acceptable rates of response and GVHD. Table 1. Patient, donor and harvest characteristics Variable N=25 Age, median(range in years) 10 (1-21) Gender, n(%) Male Female 17 (68%) 8 (32%) Diagnosis, n(%) ALL-B ALL-T AML CML 16 (64%) 2 (8%) 5 (20%) 2 (8%) Time from diagnosis to transplant (months) 17.2 (1.9-153.5) Conditioning regimen, n(%) Cy 1500mg/m2 + Flu 75mg/m2 + Bu 9.6mg/kg (IV) Cy 1050mg/m2 + Flu 75mg/m2 + Bu 12 mg/kg (oral) Cy/VP-16/RT Cy/Flu/Mel 16 (64%) 6 (24%) 2 (8%) 1 (4%) Donor, n(%) Mother Father Sister 20 (80%) 3 (12%) 2 (8%) Donor age, median(range in years) 38 (17-49) Infused CD34+ x 106/kg, median(range) 11 (3.2-20) Disclosures No relevant conflicts of interest to declare.

Download Full-text

Use of Partially Mismatched Related Donors Extends Access to Allogeneic Marrow Transplant

Blood ◽

10.1182/blood.v89.10.3864.3864_3864_3872 ◽

1997 ◽

Vol 89 (10) ◽

pp. 3864-3872 ◽

Cited By ~ 3

Author(s):

P. Jean Henslee-Downey ◽

Sunil H. Abhyankar ◽

Rudolph S. Parrish ◽

Asim R. Pati ◽

Kamar T. Godder ◽

...

Keyword(s):

T Cell ◽

High Risk ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Disease Status ◽

Marrow Transplant ◽

Successful Outcome ◽

High Dose ◽

Allogeneic Bone ◽

Significant Difference

Most patients requiring allogeneic bone marrow transplant (allo-BMT) do not have an HLA-matched sibling donor. A phenotypically matched unrelated donor graft has been made available for approximately 50% of Caucasians and less than 10% of ethnic and racial minorities in need. However, almost all patients have a readily available partially mismatched related donor (PMRD). We summarize our experience with 72 patients who ranged from 1 to 50 years of age (median, 16 years) and who were recipients of a PMRD allo-BMT from haploidentical family members following conditioning therapy using total body irradiation (TBI) and multiagent, high-dose chemotherapy. T-cell depletion and post-BMT immunosuppression were combined for graft-versus-host disease (GVHD) prophylaxis. The probability of engraftment was 0.88 at 32 days. Six of 10 patients who failed to engraft achieved engraftment after secondary transplant. Grade II to IV acute GVHD was seen in 9 of 58 (16%) evaluable patients; extensive chronic GVHD was seen in 4 of 48 (8%) evaluable patients. There was a statistically significant difference in 2-year survival probability between low-risk and high-risk patients (0.55 v 0.27, P = .048). Prognostic factors that affected outcomes in multivariate analysis were (1) a lower TBI dose and 3-antigen rejection mismatch decreased stable engraftment (P = .005 and P = .002, respectively); (2) a higher T-cell dose increased acute GVHD (P = .058); (3) a higher TBI dose increased chronic GVHD (P = .016); and (4) a high-risk disease category increased treatment failure from relapse or death (P = .037). A PMRD transplant can be performed with acceptable rates of graft failure and GVHD. Using sequential immunomodulation, the disease status at the time of transplant is the only prognostic factor significantly associated with long-term successful outcome after PMRD allo-BMT. When allogeneic rather than autologous BMT is indicated, progression in disease status before transplant can be avoided using a PMRD with equal inclusion of all ethnic or racial groups.

Download Full-text

CD34-Selected, T Cell-Depleted Alternative Donor Stem Cell Transplantation For Children

Blood ◽

10.1182/blood.v122.21.2064.2064 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2064-2064 ◽

Cited By ~ 1

Author(s):

Andrew Gilman ◽

Michael Eckrich ◽

Stacy Epstein ◽

Carrie Barnhart ◽

Javier Oesterheld ◽

...

Keyword(s):

Stem Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Post Transplant ◽

Primary Graft Failure ◽

Alternative Donor ◽

Mast Cell Leukemia ◽

Grade Ii

Abstract Many children who need a hematopoietic stem cell transplant do not have a matched related or unrelated donor. The use of alternative donors including mismatched family members can provide a donor for almost all patients. The use of such donors is associated with a high risk of graft-versus-host disease (GVHD). We present the results of a prospective study using the CliniMACS® device for CD34-selection of peripheral blood stem cell (PBSC) grafts to prevent GVHD under BB-IND 14045. Patients did not receive immunosuppression after transplant. The approach was also used as a platform for a companion post-transplant immunotherapy study. The study included patients with malignant (MD) and non-malignant (NMD) disorders receiving unrelated donor (UD) and mismatched related donors (MMRD) to evaluate the broad applicability of this approach for GVHD prevention. The primary endpoint was acute GVHD incidence and there was a stopping rule for primary graft failure. Overall survival was a secondary endpoint. Between 2009-2013, 30 children underwent CD34-selected PBSC transplantation from an alternative donor. Fifteen patients had MD (ALL 4, AML 8, JMML 1, acute mast cell leukemia 1, Ewing’s sarcoma 1) and 15 had NMD (sickle cell 6, immunodeficiency 5, bone marrow failure 4). Twenty-three patients had MMRD and 7 had UD (all 7 had NMD). The conditioning regimen consisted of TBI 1200 cGy (MD) or melphalan 140mg/m2 (NMD), thiotepa 5mg/kg x2, fludarabine 40 mg/m2x5, and rabbit-ATG 1.5 (MD) or 2.5 (NMD) mg/kg x4. Seven patients with NMD received rituximab x1 during conditioning. Twenty-two patients received a planned (P) donor lymphocyte infusion (DLI) between days 30 and 42 with methotrexate GVHD prophylaxis on a companion study. Eight patients received a therapeutic (T) DLI for decreasing donor chimerism or viral infection. The median age at transplantation was 10 years (range 0.3-17). Median CD34+ dose was 21 x 10^6/kg (range 10-25) and all patients received < 1 x 10^4 CD3/kg. The ANC was > 500 at median 14 days (range 9-16). Acute GVHD prior to DLI occurred in 1 patient (3%; stage I skin which resolved with a brief course of prednisone). Primary graft failure occurred in 1 patient (3%). The patient subsequently engrafted after a CD34-selected transplant from the other parent. Two patients who had active disease at transplant (mast cell leukemia, Ewing’s) and early relapse are excluded from the following analyses. Twenty-one of 28 patients are alive with median follow-up of 2 years (range 1 mo-4 yrs). The Kaplan-Meier estimated 100 day and 1 year survival is 96% and 74%, respectively. Relapse occurred in 1/10 MD patients with at least 100 days follow-up. Grade II-IV acute GVHD and chronic GVHD occurred only after DLI. Acute GVHD grade II-IV occurred in 21% (3 P, 3 T) and chronic GVHD (3 P) in 11%. Viral reactivation was common, but viral disease was less common - CMV 12% and EBV-related PTLD 11% [at risk patients only] and adenovirus 11%. Invasive fungal infections occurred in 7%. All deaths were due to infection, with thrombotic microangiopathy present in 6/7. All outcomes were similar for MD and NMD and for MMRD and UD except for acute GVHD which occurred in 26% MMRD and 0% UD transplants and for EBV-PTLD which only occurred in NMD patients. EBV-PTLD has been reduced in NMD patients by using rituximab in the conditioning. The use of a CD34-selected, T cell-depleted alternative donor PBSC transplant successfully prevented acute GVHD without the need for post-transplant immunosuppression. The use of this approach and the conditioning regimens employed provided reliable engraftment and a very low incidence of Day 100 transplant-related mortality and relapse (for patients without active disease). Future efforts will focus on approaches for post-transplant immunotherapy to decrease morbidity and mortality due to viral infections. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Prospective Phase II Study of Prophylactic Azacitidine and Donor Lymphocyte Infusions Following Allogeneic Hematopoietic Stem Cell Transplantation for High Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome

Blood ◽

10.1182/blood.v128.22.1162.1162 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1162-1162 ◽

Cited By ~ 7

Author(s):

Thierry Guillaume ◽

Ibrahim Yakoub-Agha ◽

Reza Tabrizi ◽

Cecile Borel ◽

Patrice Chevallier ◽

...

Keyword(s):

Heart Failure ◽

Immune Response ◽

Stem Cell ◽

High Risk ◽

Prophylactic Treatment ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Post Transplantation ◽

Hematopoietic Stem ◽

Post Transplant

Abstract Although allogeneic hematopoietic stem cell transplantation is presently the only curative option for many patients with AML or MDS, relapse remains the main cause of morbidity and mortality. Strategies are therefore developed to prevent relapse. Post-transplant immune intervention with administration of prophylactic or pre-emptive donor lymphocyte infusion (DLI) and/or chemotherapy maintenance using DNA-demethylating agents such as azacitidine (aza) is being investigated. The exact mechanism of action of aza remains obscure and might be due in part to tumor antigen upregulation or other gene induction by tumor cells causing an immune response. We enrolled, in a clinical trial (ClinicalTrials.gov Identifier:NCT01541280), patients (pts) with high risk AML or MDS and candidates for allo-HSCT transplantation to receive azacitidine (aza) and DLI post-transplant as prophylactic treatment with the primary objective to reduce the relapse rate at 2 years following allo-HSCT and secondary objectives to increase disease free survival at 2 years post-transplant, increase overall survival at 2 years, investigate feasibility and safety of maintenance strategy combining chemotherapy and immunotherapy and follow the incidence and severity of acute and chronic GVHD. High risk AML was defined as AML in CR1 with unfavorable cytogenetics, AML in CR2 or greater remission, refractory AML or in relapse prior allogeneic transplantation. High risk MDS was defined as MDS with intermediate-2 group and higher risk group according to IPSS criteria. Aza was scheduled to begin between d+56 and d+112 post-transplant at the doses of 32 mg/m²/d sc for 5 days every 28 days for up to a total of 12 cycles if the pt had not acute GVHD >1 or severe infection. The first DLI was started following 3 cycles of aza and discontinuation of immunosuppressive prophylaxis, and if the pt had no clinical signs of GVHD, uncontrolled infection or a recent history of gr>2 acute GVHD. Two other DLI were scheduled every 8 weeks after the 5th and 7th cycle of aza. The doses of DLI 1, 2 and 3 were respectively 5x106, 1x107, 5x107 CD3+cells/kg for related donor, and 1x106, 5x106, 1x107 CD3+cells/kg for unrelated donor. Sixty-four patients were pre-included prior transplantation, 30 pts were subsequently included, 20 pts with AML and 10 pts with MDS, median age 58 y (22-70). The status at transplantation was: CR1 = 16 pts (53%), CR2 = 6 pts (20%), refractory = 5 pts (16%), upfront transplantation for MDS = 3 pts (10%). Cytogenetics was normal or intermediate for 15 pts and unfavorable for 15 pts (namely 8 pts with complex caryotype). Conditioning was myeloablative for 11 pts, reduced for 19 pts (including 2 sequential). Donors were unrelated volunteers in 18 pts (60%).The time between allografting and first aza cycle was 66 days (38-93). The median number of cycles of aza administered was 5 (1-12) with 10 pts (33%) completing the 12 cycles. Forty one DLI were injected in 17 pts: 5 pts received one DLI, 2 pts received 2 DLI, 8 pts received 3 DLI. Two additional pts received 4 and 5 DLI because of a mixed chimerism. The first DLI was given at a median of 142 d (129-221) post transplantation. Aza was well tolerated, but was discontinued in 20 pts: because of GVHD (n=11), relapse (n=5), GVHD/infection (1pt), sudden death due to heart failure (n=1), withdrawal of consent (n=2, one after 1 cycle and another after 5 cycles). Four months following transplantation, 24 (80%) demonstrated full donor chimerism (>95%) in CD3+ cells. Nine patients developed grade 1 to 3 acute GVHD (CI 29.8±9%), 6 who did not receive DLI and 3 following DLI (grade 1 n=2, grade 2 n=3, grade 3 n=4). No grade 4 acute GVHD was observed. Nine pts developed chronic GVHD (2 limited, 7 extensive), 3 who did not receive DLI, 6 following DLI. Twenty patients are alive. With a median follow-up from the allotransplant for those alive of 36 months (range 12 - 46 months), the survival at three years is 66%. Causes of death were infection (n=1), relapse (n=8), sudden death due to heart failure (n=1). The median time to relapse was 5 months (2.5-9) and the cumulative incidence of relapse at 3 years 28.1±8.5%. These results confirm that aza is well tolerated as a prophylactic treatment to reduce the risk of post-transplantation relapse. The incidence of GVHD following aza + DLI was not overwhelming. Analysis of T cell population and immune response as well as comparison to matched-pair control are currently performed and will be presented. Disclosures Moreau: Amgen: Honoraria; Novartis: Honoraria; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria.

Download Full-text

ANTI-CMV Immunoglobulins in Association with ANTI-CMV Drugs in Patients with Hematological Malignancies Submitted to Allogeneic STEM CELL Transplantation: A MULTI-Center Retrospective Experience

Blood ◽

10.1182/blood-2018-99-110252 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3381-3381

Author(s):

Michele Malagola ◽

Jacopo Peccatori ◽

Raffaella Greco ◽

Francesca Serio ◽

Stella Santarone ◽

...

Keyword(s):

Risk Factors ◽

Stem Cell ◽

High Risk ◽

Hematological Malignancies ◽

Cord Blood Transplantation ◽

Advisory Board ◽

High Dose ◽

Specific Drug ◽

Cmv Reactivation

Abstract CMV represents one of the most serious life-threatening complications of allogeneic stem cell transplantaion (allo-SCT). Pre-emptive treatment with anti-CMV drugs is highly effective, but toxicity and repetitive reactivation of CMV represent a major challenge in the clinical practice. The use of anti-CMV specific immunoglobulins (Megalotect) is controversial. We retrospectively collected data on 539 patients with hematological malignancies submitted to allo-SCT in 6 Italian Bone Marrow Transplant Units between 2016 and 2017. Two hundred and forty two of the 539 patients (45%) developed at least one CMV reactivation. In 94/242 cases (39%) Megalotect was used according to internal guidelines. This report focuses on this group of 94 patient. Megalotect was used as prophylaxis in 15/94 cases (16%) and as pre-emptive therapy together with a specific anti-CMV drug in 79/94 cases (84%). Fifty-six out of 94 cases (60%) received 50 UI/Kg weekly, 33/94 cases (35%) received 50 U/Kg every 2-3 weeks (the remaining patients received different doses and schedule according to the Center policy). Megalotect was used because all the 94 patients were considered at high risk of developing repetitive CMV reactivation. In the prophylaxis setting these risk factors were: haploidentical and cord blood transplantation in 5 cases and unfavorable CMV sireology combiation in 14 cases. In the pre-emptive setting, the risk factors were: haploidentical transplantation in 30 cases, aGVHD requiring high-dose steroids in 37 cases and unfavourable CMV serology combination (D-/R- in 44 cases, D+/R- in 1 case). In the pre-emptive setting the following anti-CMV drugs were used first-line: gancyclovir (31 cases), foscarnet (19 cases), valgancyclovir (14 cases), different combinations (15 cases). Overall, the treatment was well tolerated, with no reported infusion reactions nor other adverse events. Megalotect was administered for a median of 2 doses (range 1-9) and 3 doses (range 1-33) in patients treated prophylactically or pre-emptively. None of the 15 cases treated with Megalotect as prophylaxis developed CMV reactivation. Focusing on the 79 cases treated with Megalotect pre-emptively, 59 patients (75%) achieved at least one CMV viremia negativity during tratment. Median time to first negativity was 19 days (range 3-190). In 30/79 cases (38%) a subsequent CMV reactivation was observed during the follow up, which was treated with a second-line anti-CMV specific drug. Interestingly, only 6/94 cases (6%) developed CMV disease: gut localization in 4 cases and other site in 2 cases.Overall 24/94 patients died (25%) and no death was CMV-related Our preliminary experience with Megalotect suggests that it is safe and well tolerated both in the pre-emptive and prophylaxis setting. We have no conclusive data regarding the efficacy of this treatment in reducing the cumulative dose of anti-CMV specific drugs. Interestingly, when used as prophylaxis, no CMV reactivation was recorded. In the pre-emptive setting, the combination of Megalotect and anti-CMV specific drug was able to induce negativity of CMV viremia in a relatively short time (median 19 days) and 38% of these high-risk patients only developed further CMV reactivation during follow up. Further prospective trials are warrented to address the most appropriate use of Megalotec (preophylaxis vs pre-emptive) and to identify the best setting of patients who can benefit from Megalotect alone or in addition to anti-CMV specific drugs. Disclosures Foà: ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; GILEAD: Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; INCYTE: Other: ADVISORY BOARD; NOVARTIS: Speakers Bureau; CELTRION: Other: ADVISORY BOARD; ROCHE: Other: ADVISORY BOARD, Speakers Bureau.

Download Full-text

Reduced-Intensity Conditioning (RIC) Regimen Followed by Allogeneic Stem Cell Transplantation (alloSCT) for Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLCL). A Retrospective Study from the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC) Registry.

Blood ◽

10.1182/blood.v108.11.2946.2946 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2946-2946

Author(s):

Anne Sirvent ◽

Michael Hummelsberger ◽

Zina Chir ◽

Nathalie Dhedin ◽

Catherine Faucher ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Acute Gvhd ◽

Statistical Significance ◽

Chronic Gvhd ◽

Autologous Transplantation ◽

B Cell Lymphoma ◽

Primary Therapy ◽

Hla Antigen

Abstract Despite progress in their primary therapy, nearly half of patients (PTS) with DLCL will either relapse or fail to archieve a remission. Autologous transplantation may salvage those PTS with chemosensitive disease. However, PTS with high-risk disease or relapsing after autologous transplantation have a particularly poor prognosis. AlloSCT with RIC offers the advantage of a decreased transplant-related mortality combined with a Graft-versus-Lymphoma effect explaining its increasing use in PTS who fail standard therapy. We retrospectively analyzed all PTS with DLCL reported to the SFGM-TC registry, who underwent alloSCT after RIC. 51 PTS (median age 42 years, range 22 to 64 years) were transplanted from Oct. 2002 to Oct. 2004. 23% of PTS had received > 2 lines of prior therapy and 78% had relapsed after autologous transplantation. For 22% of PTS, alloSCT was the first graft. Median time from diagnosis to alloSCT was 33 months (6–126). Disease status at time of alloSCT was: complete remission (CR) n=22, partial remission (PR) n=18, stable disease (SD) n=2, progressive disease (PD) n=7. RIC consisted of fludarabine + busulfan in 27 PTS, fludarabine + total body irradiation in 10, fludarabine + cyclophosphamide in 7 and miscellaneous combinations in 7. GVHD prophylaxis consisted of cyclosporin A (CyA) alone in 18 PTS, CyA/methotrexate in 14 PTS, CyA/mycophenolate mofetil in 14 PTS and other immunosuppressive drugs in 5 PTS. 31 PTS received antithymocyte globulin. Stem cell source was peripheral blood stem cells in 43 PTS and bone marrow in 8. 47 donors were HLA-matched siblings, 4 were unrelated (3 donors HLA-matched and 1 donor with 1 HLA antigen mismatch). Median follow-up after alloSCT was 12 months (0–72). All PTS engrafted except one who died early after transplantation. Grade II to IV acute GVHD occurred in 16 PTS and extensive chronic GVHD in 8/43 valuable PTS. Non relapse mortality was 21% (multi-organ failure : 3, acute GVHD : 1, chronic GvHD : 1, interstitial pneumonia : 1, infection : 4, neurological complication : 1, unknown origin : 1). 20 PTS progressed after a median follow-up of 4.5 months (0–29) and 10 PTS died of progressive DLCL. 23 PTS remain alive and disease-free at a median follow-up of 17 months (1–72). Overall survival is 48% at 22 months. We observe a trend for better survival without statistical significance in PTS who received alloSCT as first graft compared to >1 graft. In PTS in CR or PR prior to transplantation, Kaplan-Meier analysis demonstrates a nearly significant trend for better survival compared to non-responders (55 vs. 28%, p=0,09), but it has to be noted that 3 of 7 PTS transplanted with PD are still alive. RIC followed by alloSCT seems to be feasible even in heavily pretreated PTS and offers the perspective of long lasting remission. Further prospective studies with RIC and alloSCT earlier in the disease course or in defined high-risk PTS in first relapse as an alternative to autologous transplantation should be undertaken.

Download Full-text

A Comparison of Stem Cell Source in Adult and Paediatric Recipients of T-Cell Depleted Myeloablative Transplants for Standard Risk Leukaemia: No Difference in Mortality Using BM or PBSC.

Blood ◽

10.1182/blood.v114.22.1205.1205 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1205-1205

Author(s):

Bronwen E Shaw ◽

Jane Apperley ◽

Nigel H. Russell ◽

Charles F. Craddock ◽

Effie Liakopoulou ◽

...

Keyword(s):

Stem Cell ◽

T Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Stem Cell Source ◽

Significant Difference ◽

Cell Source ◽

Standard Risk

Abstract Abstract 1205 Poster Board I-227 The use of GSCF-mobilised Peripheral Blood Stem Cells (PBSC) for unrelated donor (UD) transplantation has increased dramatically since 2000. The association of PBSC with more rapid engraftment and with an increase in chronic Graft versus Host Disease (GvHD), compared to bone marrow (BM) has been reported in a number of studies. More recently the use of PBSC has been associated with an increase in non relapse mortality (NRM) and decrease in survival (OS) in T-cell replete transplants. We have previously reported outcome data in 145 patients who received an unrelated donor transplant for leukaemia. In that study we reported an increase in mild acute GvHD using PBSC, but no other significant differences in outcome. We have now doubled the cohort and report our findings on 320 patients here. In this group all of the patients received pre-transplant serotherapy (Alemtuzumab = 306, ATG = 14) as part of myeloablative conditioning prior to an HLA-matched UD allograft. Patients were transplanted between January 2000 and August 2007: CML in 1CP (n=102) and acute leukaemia in CR1/2 (AML in 105, ALL in 144). 190 patients received BM and 130 PBSC. The median age of the recipients was 28.9 years (10months - 58years). There was no significant difference in age between those receiving BM or PBSC.98% and 96% of patients receiving PBSC and BM achieved neutrophil engraftment (NS), with a significantly faster time to engraftment in recipients of PBSC compared to BM (14 vs 20 days; p<0.001). The incidence of acute GvHD was significantly higher in recipients of PBSC (64%) compared to BM (51%; p=0.022), however there was no increase in grade III/IV (p=0.420) disease in PBSC recipients. The incidence of chronic GvHD at 6 years was 61% in the BM recipients and 55% in the PBSC recipients (NS), with no difference in the incidence of extensive disease. The 5-years OS was 55% in BM recipients, with a median follow-up of 59 months, compared to 54% in PBSC recipients at a median follow-up of 38 months (NS). The incidence of neither disease relapse nor NRM was significantly different between groups (relapse at 5 years: BM 44%, PBSC 36%; p=0.112, and NRM at 5 years: BM 22%, PBSC 24%; p=0.751). In view of the fact that there were more CML patients in the BM group and more AML patients who received PBSC (the distribution of ALL patients was similar) (p=0.051), we performed a subgroup analysis. The pattern of results for each outcome, dependant on the use of BM or PBSC, in patients with CML and those with acute leukaemia were similar to those reported in the group overall. In conclusion, we have confirmed the results of our previous smaller study, showing the only significant difference in clinical outcome between PBSC and BM to be a higher incidence in the occurrence (but not grade) of acute GvHD. We found no association between the use of PBSC and an increased risk of chronic GVHD or of a worse transplant outcome, when compared to BM. We suggest that either stem cell source can be used with a similar outcome in adult and paediatric recipients of T-cell depleted allografts for standard risk leukaemia. Disclosures: Apperley: Novartis: Consultancy, Honoraria.

Download Full-text

Selective Depletion of T Cell Alloresponses Using a Photodepletion Strategy Preferentially Targets CD4+ T Cells.

Blood ◽

10.1182/blood.v116.21.1467.1467 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1467-1467

Author(s):

Zachariah A. McIver ◽

Andrew Grim ◽

Nicolas Naguib ◽

Hahn Khuu ◽

Minoo Battiwalla ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

T Cell ◽

Nk Cells ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Central Memory ◽

Viral Reactivation ◽

Post Transplant ◽

Selective Depletion

Abstract Abstract 1467 P-glycoprotein (Pgp) is the product of the multidrug-resistance-1 (MDR1) gene and actively transports various molecules across the extracellular membrane. Previous studies demonstrated that activated lymphocytes decrease Pgp activity and preferentially retain the photosensitizing agent 4, 5-dibromorhodamine 123 (TH9402, Kiadis Pharma, NL). We evaluated a photodepletion technique to achieve selective depletion (SD) of graft-versus-host disease (GVHD) alloreacting T cells in 24 HLA-identical sibling stem cell transplants. Donor lymphocytes were activated by 72 hr exposure with irradiated in-vitro expanded recipient T lymphocytes and pulsed with TH9402. Alloactivated T cells preferentially retaining the photosensitizer were eliminated by light exposure. The transfused cell products were then analyzed for T cell subset frequency. After SD preferential CD4+ T cell depletion occurred with an inversion of the CD4+/CD8+ ratio. Within the CD4+ compartment a significant depletion of naïve (CD27+ CD45RO-), central memory (CD27+ CD45RO+), and effector (CD27-CD45RO+) populations was noted. Conversely, CD8+ naïve and effector subsets was relatively conserved with depletion occurring predominantly in the central memory population. Additionally, an 80% reduction in B cells occurred, with a 60% reduction of cytotoxic NK cells (CD56+CD16+) and a relative expansion of regulatory NK cells (CD56+CD16-). We compared outcomes of 24 SD transplants with 34 patients receiving a T-cell depleted transplant. All patients with hematological malignancies were conditioned with fludarabine, cyclophosphamide, and total body irradiation and received a CD34-selected stem cell allograft from an HLA identical sibling. SD recipients also received 5×106/kg SD donor T cells. Low-dose cyclosporine was used as the only post-transplant immunosuppression. Median follow up was 14.5 months. The probability of severe acute GvHD (grade III-IV, 13%) and relapse (25%) was low for all patients. On day 100 post-transplant SD transplant recipients had lower absolute CD4+ counts, and increased rates of CMV reactivation requiring treatment (median 2 vs 1 reactivations within 100 days, p<0.01), and more chronic GvHD (70% vs 31%, p=0.04). Previous studies have shown that Pgp efflux of rhodamine-123 in quiescent T cells varied between subsets, with a preferential retention occurring in the CD4+ and central memory compartments (Br J Haematol. 1998 Jun;101(4):722-7). Our data is in accordance with these observations. In conclusion, while SD appeared to eliminate alloactivated T cells resulting in low frequencies of severe acute GVHD, differences in Pgp activity and dye retention led to the preferential non-specific elimination of CD4+ and central memory T cells which may have contributed to greater viral reactivation and chronic GVHD. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Calcineurin Inhibitor-Free GVHD Prophylaxis with Post-Transplant Cyclophosphamide and Brief-Course Sirolimus Results in Low Rates of Non-Relapse Mortality and Chronic GVHD Following Matched Related and Unrelated Donor Peripheral Blood Stem Cell Transplantation (PBSCT)

Blood ◽

10.1182/blood.v122.21.923.923 ◽

2013 ◽

Vol 122 (21) ◽

pp. 923-923

Author(s):

Melissa Sanacore ◽

Asad Bashey ◽

Connie A. Sizemore ◽

H. Kent Holland ◽

Lawrence E. Morris ◽

...

Keyword(s):

Stem Cell ◽

T Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Platelet Recovery ◽

Post Transplant ◽

Gvhd Prophylaxis ◽

Allogeneic Pbsct

Abstract Calcineurin inhibitors (CNIs) form the foundation of current GVHD prophylaxis regimens. Although advances in immunosuppressive regimens have had a significant impact on the incidence and severity of acute GVHD, it is noteworthy that CNIs have had little impact on chronic GVHD. We hypothesized that a CNI-free regimen consisting of post-transplant cyclophosphamide (Cy) and brief-course sirolimus would decrease the risk of chronic GVHD and non-relapse mortality and improve outcomes following reduced intensity allogeneic PBSCT. Twenty-seven patients with high risk hematologic malignancies were enrolled in the study: median age 61 years (25-73). All patients had a 10/10 locus matched donor; MRD=18, MUD=9. Conditioning consisted of fludarabine 30mg/m2 on days -9 to -6, IV busulfan 130 mg/m2 on days -5 to -4, and Cy 14.5 mg/kg on days -3 and -2 followed by unmanipulated PBSCT. Post-grafting immunosuppression consisted of Cy 50 mg/kg/day on days 3 and 4 and sirolimus starting day +5 and completing day+90 in the absence of GVHD. Donor engraftment occurred in all patients with a median time to neutrophil and platelet recovery of 15 and 30 days, respectively. The median day +90 donor T cell and myeloid chimerism was 94% (40-100%) and 100% (11-100%) respectively. Three patients received donor lymphocyte infusions for incomplete donor T cell chimerism. The cumulative incidence of grade II-IV acute GVHD, grade III-IV acute GVHD, all chronic GVHD, and severe chronic GVHD was 41%, 15%, and 32%, and 12% respectively. Non-relapse mortality (NRM) and relapse incidence at 2 years was 4% and 17% respectively. With a median follow-up of 18 months, the estimated 2 year overall and disease-free survival was 71% and 80% respectively for the whole cohort, while it was 87% and 89%, respectively in the subgroup of 18 patients receiving MRD transplants. Good immune reconstitution was evidenced by low cytomegalovirus reactivation rates, occurring in only 4 of 19 at-risk patients (21%). Transplant-related toxicity included BK virus-associated cystitis in 33% of patients and a non-fatal hepatotoxicity syndrome in three patients consisting of transaminase elevation and ascites, with resolution following discontinuation of sirolimus. CNI-free GVHD prophylaxis with post-transplant Cy and brief-course sirolimus achieves consistent donor engraftment, low rates of GVHD and NRM, and excellent outcomes in recipients of HLA-identical donor allogeneic PBSCT. Disclosures: Off Label Use:fludarabine, cyclophosphamide, and sirolimus are not FDA-labeled for stem cell transplantation.

Download Full-text

Haploidentical Hematopoietic Cell Transplantation Using G-CSF Mobilized T-Cell Replete Grafts for for Acute Leukemia and MDS

Blood ◽

10.1182/blood.v128.22.2278.2278 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2278-2278

Author(s):

Eric Huselton ◽

Rizwan Romee ◽

Michael Slade ◽

Cory Jenson

Keyword(s):

T Cell ◽

High Risk ◽

Relapse Rate ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Post Transplant ◽

Active Disease ◽

Treatment Related Mortality ◽

Related Mortality

Abstract The use of T-cell replete grafts from MHC-haploidentical donors with post-transplant cyclophosphamide (PTCy) to selectively deplete alloreactive T cells is efficacious in patients who do not have ready access to an HLA identical donor. The Johns Hopkins group that pioneered this regimen used non-myeloablative (NMA) conditioning and bone marrow (BM) grafts to help mitigate the risk of GvHD. Their results showed low rates of GvHD and treatment related mortality but outcomes were limited by a high relapse rate. However, for patients with active disease or other high risk characteristics new approaches are needed to help mitigate post-transplant relapse. For other transplant modalities, peripheral blood stem cell (PBSC) grafts are associated with lower relapse rates, faster engraftment, and improved overall survival when compared to BM derived grafts. To date, there are few small studies evaluating the outcomes G-CSF mobilized PBSC grafts for haplo-HCT with PTCy. To report our experience with T cell replete PBSC grafts with PTCy for haplo-HCT, we retrospectively analyzed the outcomes of patients with leukemia and MDS who underwent this transplant regimen. Between 2009 and 2015, 124 patients were transplanted at Washington University School of Medicine with this transplant platform and their outcomes were measured by retrospective chart review through June 2016. Donors were mobilized with G-CSF 10 mcg/kg daily for 5 days prior to beginning pheresis and no grafts were subjected to ex vivo T-cell depletion. Myeloablative conditioning was used for 54 patients and NMA regimens were used for 70 patients, after which, patients were infused with a median of 5.0 x 106 CD34+ cells/kg and 18.0 x 107 CD3+ cells/kg. For GvHD prophylaxis, all patients received PTCy 50 mg/kg on days +3 and +4, tacrolimus from day +5 to 180, and mycophenolate mofetil from day +5 to 35, as previously described. The median age at time of haplo-HCT was 53 years (range 19-73). Ninety three patients were transplanted for AML, 16 for ALL, and 15 for MDS. This was a high risk population with a median Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score of 3.5 (≥3 indicates high risk). Thirty two patients had prior transplants and 49 patients had active disease prior to their transplant. Median follow up for surviving patients was 553 days. Neutrophil count recovery occurred after a median of 17 days and platelet recovery after 29 days. 74 patient deaths occurred by June 2016. Relapse accounted for 36 deaths, infection for 17, acute GvHD for 9, graft failure for 3, and 9 patients died from other causes. The 1 year overall survival (OS) was 47.5% (95% CI 38.2-56.2%) and 1 year event free survival was 40.2 (31.2-48.9%). For patients transplanted in remission, 1 year OS was 50.8% (38.7-61.6%), while for patients transplanted with active disease 1 year survival was 42.9% (28.4-56.5%). Treatment related mortality at 6 months and 1 year was 20.2% (13.7-27.8%) and 31.4% (23.1-40.0%). The relapse rate at 1 year was 39.5% (28.7-50.1%). For patients transplanted in remission, the 1 year relapse rate was 31.4% (18.7-44.9%) and for those transplanted with active disease it was 50.7% (32.5-66.3%). Univariate analysis showed increased risk of relapse when going into transplant with active disease or receiving NMA regimens. The 180 day cumulative incidence of grades II-IV acute GvHD was 39.3% (30.0-48.9%) and grade III-IV acute GvHD was 10.8% (3.1-23.7%). 1 year cumulative incidence of chronic GvHD was 49.0 (35.8-60.9%) and severe chronic GvHD was very low at 4.0% (1.0-10.4%). In conclusion, using G-CSF mobilized grafts from PBSC for haplo HCT with PTCy is feasible for patients with leukemia and MDS who do not have ready access to an HLA identical donor. The use of PBSC grafts with higher numbers of CD3+ cells led to rapid engraftment, low rates of graft failure, and acceptable rates of acute and chronic GvHD. The 1 year OS was almost 1 year, which is encouraging considering most patients had a HCT CI score > 3 and many had active disease at transplant or already failed a prior transplant. Disease relapse post-transplant remains the primary cause of post-transplant mortality for these leukemia patients. In this cohort relapse was associated with having active disease at time of transplant and receiving NMA conditioning. Our results show using PBSC may be a valid alternative to bone marrow grafts for haplo HCT with PTCy. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Use of Partially Mismatched Related Donors Extends Access to Allogeneic Marrow Transplant

Blood ◽

10.1182/blood.v89.10.3864 ◽

1997 ◽

Vol 89 (10) ◽

pp. 3864-3872 ◽

Cited By ~ 160

Author(s):

P. Jean Henslee-Downey ◽

Sunil H. Abhyankar ◽

Rudolph S. Parrish ◽

Asim R. Pati ◽

Kamar T. Godder ◽

...

Keyword(s):

T Cell ◽

High Risk ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Disease Status ◽

Marrow Transplant ◽

Successful Outcome ◽

High Dose ◽

Allogeneic Bone ◽

Significant Difference

Abstract Most patients requiring allogeneic bone marrow transplant (allo-BMT) do not have an HLA-matched sibling donor. A phenotypically matched unrelated donor graft has been made available for approximately 50% of Caucasians and less than 10% of ethnic and racial minorities in need. However, almost all patients have a readily available partially mismatched related donor (PMRD). We summarize our experience with 72 patients who ranged from 1 to 50 years of age (median, 16 years) and who were recipients of a PMRD allo-BMT from haploidentical family members following conditioning therapy using total body irradiation (TBI) and multiagent, high-dose chemotherapy. T-cell depletion and post-BMT immunosuppression were combined for graft-versus-host disease (GVHD) prophylaxis. The probability of engraftment was 0.88 at 32 days. Six of 10 patients who failed to engraft achieved engraftment after secondary transplant. Grade II to IV acute GVHD was seen in 9 of 58 (16%) evaluable patients; extensive chronic GVHD was seen in 4 of 48 (8%) evaluable patients. There was a statistically significant difference in 2-year survival probability between low-risk and high-risk patients (0.55 v 0.27, P = .048). Prognostic factors that affected outcomes in multivariate analysis were (1) a lower TBI dose and 3-antigen rejection mismatch decreased stable engraftment (P = .005 and P = .002, respectively); (2) a higher T-cell dose increased acute GVHD (P = .058); (3) a higher TBI dose increased chronic GVHD (P = .016); and (4) a high-risk disease category increased treatment failure from relapse or death (P = .037). A PMRD transplant can be performed with acceptable rates of graft failure and GVHD. Using sequential immunomodulation, the disease status at the time of transplant is the only prognostic factor significantly associated with long-term successful outcome after PMRD allo-BMT. When allogeneic rather than autologous BMT is indicated, progression in disease status before transplant can be avoided using a PMRD with equal inclusion of all ethnic or racial groups.

Download Full-text