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Background

BACKROUND:Hodgkin Lymphoma (HL) is characterized by a high degree of response to chemotherapy and an overall favorable outcome in responding patients. Despite the efficacy of first line therapy, however, about 30% of patients affected by HL eventually relapse or are refractory (R/R) to first or second line therapy followed by autologous hemopoietic stem cell transplantation (ASCT).

No relevant conflicts of interest to declare.

Gobbi: Amgen: Consultancy; Ariad: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Pfister: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy.

BACKROUND

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Introduction.Allogeneic stem cell transplantation remains the only curative therapy for patients with myelofibrosis, but is associated with relevant morbidity and mortality, possiby due to the specific nature of the disease. The outcome is significantly worse when alternative donor transplants are compared to matched siblings (MSD): in a recent cooperative study, TRM was 22% in MSD vs 59% in patients receiving unrelated donor grafts (UD) (Blood 2014 124:1183).

Leukemia relapse remains a significant problem in patients with AML undergoing an allogeneic stem cell transplant(HSCT). Wilms Tumour 1 (WT1)expression has been shown to be a sensitive marker of minimal residual disease (MRD), both in patients after induction chemotherapy, as well as in patients undergoing an allogeneic HSCT.

We have previously defined poor graft function (PGF) as 2 or 3 cytopenic lines (Hb<10 g/dl, neutrophil count <1,0 x 10^9/L, platelet count <30 x 10^9/L), lasting for at least 2 consecutive weeks post-transplant, beyond day +14, with transfusion requirement, associated with hypoplastic-aplastic bone marrow, in the presence of complete donor chimerism and in the absence of severe GVHD and relapse (Larocca 2006). We have also shown that PGF can be treated with the infusion of donor CD34+ cells, selected from mobilized peripheral blood. (Larocca 2006) .To update the 2006 study in 41 patients.All 43 patients received a boost of CD34+ selected peripheral blood stem cells (PBSC) without prior conditioning and without GvHD prophylaxis. The median age of patients was 37 years (18-60y). The median number of CD34+ PBSC infused was 3.45 x106/Kg at median days of 140 days from 1st HSCT.Complete response, or tri-lineage recovery was defined as achieving Hb >10 g/dl, ANC > 1000 x109/L, platelets > 100.000 x 109/L. A partial recovery was defined as transfusion independence, without a complete hematologic recovery. The median follow up was 1245 days.Tri-lineage recovery was seen in 31/41 (76%) and 3/43 patients became transfusion independent, for an overall response of 83%). The median time for complete hematological recovery from CD34+ boost infusion was 183 days.There was no influence on tri-lineage recovery of the following factors : dose of CD34 cells ( 3.3) (78% vs 72%), nor patient age (35 years) 75% vs 76%, nor donor type (HLA id sib 83%, UD 79%, family mm 68%). All the patients who achieved tri-lineage recovery are alive and disease free (28/41 patients). In this cohort 13 patients died due to relapse 9/14 (64%) or GVHD 2/14 (14%) or other causes 2/14 (14%). The overall actuarial survival is 63% with a median follow up of 1245 days (94-4151 days).We confirm that infusion of CD34+ selected PBSC is associated with a high rates of tri-lineage recovery, with low risk of acute or chronic GVHD in patients who develop poor graft function following an HSCT. Tri-lineage recovery or achieving transfusion independency have an interesting impact either on disease free and overall survival. No relevant conflicts of interest to declare.

We have previously defined poor graft function (PGF) as 2 or 3 cytopenic lines (Hb<10 g/dl, neutrophil count <1,0 x 10^9/L, platelet count <30 x 10^9/L), lasting for at least 2 consecutive weeks post-transplant, beyond day +14, with transfusion requirement, associated with hypoplastic-aplastic bone marrow, in the presence of complete donor chimerism and in the absence of severe GVHD and relapse (Larocca 2006). We have also shown that PGF can be treated with the infusion of donor CD34+ cells, selected from mobilized peripheral blood. (Larocca 2006) .

In the haploidentical setting, the use of donor lymphocyte infusions (DLI) is associated with a significant risk of acute and chronic graft vs host disease (GvHD): in one report, a median T-cell dose of 2.4 × 10⋀8/kg was administered to recipients of unmanipulated haploidentical stem cell transplants, and a cumulative incidence of chronic GVHD of 50% was reported (Huang X, BBMT 2009). It is possible that patients receiving high dose Cyclophosphamide post-transplant (PT-CY) may be able to receive DLI with a lower risk of GvHDWe tested the feasibility and occurrence of GVHD, following 32 DLI administered in sixteen patients, who relapsed after an unmanipulated haploidentical T-cell replete BMT, and PT-CY.All sixteen patients were transplanted from haploidentical related donor, after a myeloablative conditioning (n=10) or a non myeloablative conditioning (n=6) with PT-CY as GVHD prophylaxis, in association with CyA and micophenolate. The diagnosis was Hodgkin's lymphoma (n 6), acute lymphoblastic B-cell leukemia (n=3), acute myeloid leukemia (n=5), pro-lymphocytic T-cell leukemia (n=1), chronic myeloid leukemia blast crisis (n=1). The median time of relapse was 211 days from transplant (range 45–697 days); the median time at DLI was 48 days from relapse (range 29–540 days) and 252 days from transplant (range 109–690). Ten patients had hematologic relapse, while six had molecular relapse.At time of first DLI all patients were off GVHD prophylaxis.The minimum dose of lymphocytes was 1 × 103̂/kg (n=2); higher doses were as follows: 1 × 104̂/kg (n=13), 1 × 105̂/kg (n=11), 5 × 105̂/kg (n=4), 1 × 106̂/kg (n=2). The median number of DLI/patient, was 1 (range 1–5). In eleven cases DLI followed chemotherapy: gemcitabine or bendamustine in Hodgkin's lymphoma and pro-lymphocytic leukemia; fludarabine, ara-C and antracycline containing regimens in acute leukemia. Median time of DLI was 12 days from chemotherapy (range 10–14 days), during the chemotherapy-induced nadir. Five patients received DLI alone.The infusions were well tolerated and no major adverse effect was observed.The cumulative incidence of acute GvHD grade II-III, was 6%, and 0% for chronic GVHD. No aplasia related to haplo-DLI occurred.Five patients died with progressive disease; 11 patients are surviving (69%), 4 of them are disease-free, seven have active disease; two patients relapsed after 313 and 135 days from DLI, respectively. The median follow-up is 221 days (range 46–559 days).This study suggests that patients grafted with haplo-mismatched BMT and high dose post-transplant cyclophosphamide, can be treated with DLI at doses up to 1× 106̂/kg, with a very low risk of developing acute or chronic GVHD.No relevant conflicts of interest to declare.

Abstract 1950

Background. Cord blood transplants (CBT) are associated with delayed or failed engraftment in a significant proportion of patients (pts). Two of our previous observations suggested (i) that, in the animal model, direct intra-bone (i.b.) injection improves seeding efficiency and (ii) that the delayed engraftment was not related to an insufficient number of hematopoietic stem cells but rather to some difficulties to differentiate and maturate. Methods. Unrelated CB cells were selected for 29 consecutive pts (18 CB units were 4/6 HLA antigen matched, 10 were 5/6 and one 3/6 antigen matched). Median cell dose infused was 2.3 x10^7/kg (range 1.4 – 4.2). CB cells were concentrated in 4 syringes of 5 ml each and injected in the supero-posterior iliac crest (SPIC) under rapid general anesthesia (10 min. with propofol). Pts’ median age was 38 years (18–63); 25 had acute leukaemia (21 with refractory or relapsed disease and 4 high risk first remission leukemia); 2 chronic myeloid leukemia in advanced phase; 2 refractory Hodgkin’s disease. Most pts (n=24) were prepared with conventional conditioning regimen (TBI-cyclophosphamide). Results. The infusion of cells i.b. in SPIC (11 pts bilaterally; 18 pts monolaterally) was uneventful. Five pts are not evaluable because they died within 14 days from transplant. All pts surviving more than 14 days engrafted (100%). Median time for PMN (>0.5x10^9/l) and platelets (>20x10^9/l) engraftment was day +23 (14–40) and +38 (range 22–60) respectivelly. Four pts died of infection; one patient died of PTLD on day +140. Four patients relasped and 3 died of relapse. Fifteen out of 16 alive patients are in hematologic or molecular remission at a median follow up of 7.5 months (range 2–17). From day +30 full donor chimerism was documented in CD3, bone marrow cells and progenitor cells from both the injected and in non-injected SPIC; from day +30, CFC progenitors had already reached the lower values of the range of normal individuals in bilateral sites. These findings document the colonization of the hematopoietc system and the recovery of stem cell reservoir possibly due to an improvement of seeding efficiency. Only 3 pts (8%) experienced acute GvHD (2 grade II and 1 grade I); 4 pts. have moderate chronic GVHD. It is known that lymphocyte trafficking is one of the crucial factor in immunity. Two combined factors might contribute to the low incidence of acute GvHD: few of the transplanted T cells do not reach/circulate primarily in the lymphatic organs, where they would be immediately confronted with host antigen presenting cells as probably occurs after i.v. injection; injected T cells come immediately in contact with mesenchymal stem cells (MSC) and osteoblasts, known to be potent immunosuppressants. Conclusion. Direct intra-bone transplant of CB cells overcomes the problem of graft failure and is associated with reduced incidence of acute GvHD even when low numbers of HLA mismatched CB cells are transplanted. Nearly all patients searching for a CB unit were able to undergo CBT. This approach may change our policy of hemopoietic cell transplants.

Background.Cord blood transplants (CBT) are associated with delayed or failed engraftment in a significant proportion of patients (pts). Two of our previous observations suggested (i) that, in the animal model, direct intra-bone (i.b.) injection improves seeding efficiency and (ii) that the delayed engraftment was not related to an insufficient number of hematopoietic stem cells but rather to some difficulties to differentiate and maturate.