Immune reconstitution, infectious complications and post transplant supportive care measures after autologous blood and marrow transplantation in children

Introduction a major limitation of hematopoietic stem cell transplantation (HSCT) from haploidentical donor is the impaired immune reconstitution due to extensive immunosuppression necessary to overcome HLA disparity. Recently, a platform for T-cell repleted HSCT from haploidentical donor (haplo-HSCT) using post-transplant cyclophosphamide (CTX) has been reported, with low TRM and high reproducibility. However, little has been reported so far about immune reconstitution and, in particular, incidence of infections after this type of transplantation. Aims of the study to describe infectious complications after T-cell replete haplo-HSCT after NMA conditioning performed at our center and to compare them with HLA-identical transplantations performed at the same center. Patients and Methods data on patients with hematological malignancies who underwent haplo-HSCT were collected and compared with RIC/NMA-HSCT from HLA-identical donors. Transplants included were those performed up to 31st December 2012. Infections were classified as FUO, bacterial, micotic or viral and prevalence over five post-transplant intervals was estimated: days 0-30, 31-100, 101-180, 181-365, >365. Prevalence for each time period was defined as the number of infectious events/patients at risk. Results we identified a total of 72 and 40 patients transplanted from HLA-identical or haploidentical donor respectively. Median follow-up was longer in HLA-identical vs. haploidentical (34 vs. 15 months, p<0.0001). Among 38 out of 40 haplo-HSCT patients, a total of 96 infectious events occurred, with a median of 3 events/patient (range: 0-6). Etiologies were as follows: 39 bacterial, 6 fungal and 51 viral. Bacterial infections occurred mostly between day 0 and +30, whereas viral infections/reactivations between +30 and +100 (see Figure 1a). In the HLA-identical cohort, 166 events occurred among 64 out of 72 patients, with a median of 2 events/patient (range: 0-8); etiologies were: 84 bacterial, 9 fungal and 73 viral. FUO events were 19 and 34 among haplo- and HLA-identical transplants respectively. Prevalence of infections was lower in HLA-identical compared with haplo-HSCT group, but subdistribution of etiologies was similar overtime (see Figure 1b), with bacterial and FUO mostly before day+30 and viral events mostly between +30 and +100. Importantly, no fungal infections occurred beyond day +180 in haplo group, probably due to the low incidence of chronic GVH. Conversely, higher prevalence of bacterial events observed in HLA-identical group may be due to chronic GVH. Deaths due infection were 25% in haplo group (10/40, occuring between +13 and +152) and 11% (8/75) among HLA-identical transplants. Conclusion RIC haplo-SCT with post-transplant CTX shows a slightly higher rate of infectious complications compared with HLA-identical ones. Subdistribution of etiologies is similar, with the highest prevalence of viral infections between +30 and +100 and no fungal events after +180. Thus, in haplo-SCT, immunological recovery appears to be satisfactory after +180. Future comparisons with other alternative stem cell sources (i.e. cord blood) are warranted. Disclosures: No relevant conflicts of interest to declare.

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Post-Transplant Cyclophosphamide and Bortezomib Combination for Prevention of GvHD after Allogeneic Blood and Marrow Transplantation Is Feasible and Produces Favorable Outcomes

Blood ◽

10.1182/blood.v124.21.3920.3920 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3920-3920

Author(s):

A. Samer Al-Homsi ◽

Tara S Roy ◽

Kelli Cole ◽

Marlee Bogema ◽

Stephanie F Williams ◽

...

Keyword(s):

T Cells ◽

Marrow Transplantation ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Post Transplant ◽

Blood And Marrow Transplantation ◽

Gvhd Prophylaxis ◽

Cmv Reactivation ◽

Grade Iii

Abstract Graft versus host disease (GvHD) remains a major barrier to the progress of blood and marrow transplantation and limits its wide applicability. Standard prophylactic regimens essentially targeting T lymphocytes are partially effective and burdensome. Cyclophosphamide (Cy) administered post-transplant selectively deletes alloreactive proliferating T cells, promotes expansion of regulatory T cells, and induces long-lasting depletion of intrathymic host-reactive T cells. It is an attractive option for prevention of GvHD and has already been used alone in matched related and unrelated donor transplants. However, despite a low incidence of chronic GvHD, acute GvHD still occurs in 50% of cases and is grade III-IV in 15% of cases. Dendritic cells (DCs) play a pivotal role in the early phase of GvHD. Proteasome inhibitors such as bortezomib (Bor) have a number of immunomodulatory effects including inhibition of DCs maturation and function. We therefore initiated a phase I feasibility study combining post-transplant Cy & Bor. Twelve patients with hematological malignancies undergoing peripheral blood allogeneic transplantation from matched related (n=6) or unrelated (n=6) donors have so far been enrolled. Disease risk index (DRI) was low in 4, intermediate in 3 and high or very high in 5. The conditioning regimen combined fludarabine and busulfan (total 6.4 mg/kg). Patients receiving graft from unrelated donors also received rabbit anti-thymocyte globulin at 5-8 mg/kg. The dose of Bor was escalated in standard fashion. Three patients in each of cohorts 1 and 2 received 0.7 and 1 mg/m2 respectively. The subsequent 6 patients received 1.3 mg/m2. All patients received 2 IV doses, 6 hours after graft infusion and 72 hours thereafter. Cy was given at 50 mg/kg IV on days +3 and +4. Steroids were not allowed after day 0. Engraftment was prompt in all patients. Median time to neutrophil engraftment was 15.5 days (range 14-25). One patient failed to meet criteria for platelet engraftment. The patient had acyclovir-resistant herpes genitalis and CMV reactivation requiring protracted therapy with foscarnet. The remaining patients had a median time to platelet recovery of 28 days (range 15-109). All patients achieved full chimerism by day 20 except one who had residual CLL and did not reach full chimerism until day +119. No patient developed secondary graft failure. Two treatment-related deaths occurred on day +150 due to RSV pneumonitis and on day +200 due to acute sepsis. One patient with recurrent multiple myeloma after autologous transplantation died due to progressive disease. No other Common Toxicity Criteria grade 3 or 4 occurred in any patient. With a median follow-up of 21 months (range 1-27), the overall 2-year predicted disease free survival and overall survival were both 60%. Incidence of acute GvHD in 11 patients with follow-up > 100 days, was 64%: grade I 55%, grade II 9%, and grade III-IV 0%. GI and liver acute GvHD were not encountered. Only 4 patients received systemic steroids for acute GvHD; only one required > 20 mg/day of prednisone. One patient developed chronic GvHD of the liver (biopsy-proven). Another patient developed poor appetite and weight loss on day +138. Endoscopy showed gastric ulceration. No biopsy was obtained. Neither calcineurin nor m-TOR inhibitors were ever used. Two patients developed extensive HSV-genito-rectal ulcers; one had prior history of recurrent flares. When institutional guidelines were changed to start acyclovir at the beginning of conditioning as opposed to day +5, no other cases was noted. Seven patients developed CMV reactivation and required preemptive therapy only. One patient developed BK virus-induced hematuria and 1 patient developed CNS toxoplasmosis. In summary, the calcineurin and m-TOR inhibitor-free post-transplant Cy & Bor combination for GvHD prophylaxis is feasible and safe. Although the small number of patients prevents any definite conclusion, the absence of incidence of grade III-IV acute GvHD and the sparing of the GI tract and liver are promising. Furthermore, the completion of GvHD prophylaxis by day +4 without the need for close renal and drug level monitoring are both practical and appealing. Updated results with longer follow-up will be reported at the meeting. A confirmatory phase II study is underway. Disclosures Al-Homsi: Millennium Pharmaceuticals: Research Funding. Off Label Use: Bortezomib use for aGvHD prevention.

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T-Cell Depleted Haematopoietic Stem Cells (HSC) Transplantation with Add Back of CD45RA Negative DLI: About 2 Cases

Blood ◽

10.1182/blood.v120.21.4350.4350 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4350-4350

Author(s):

Liliane Liliane Dal-Cortivo ◽

Rita Creidy ◽

Aurélie Gabrion ◽

Sébastien Héritier ◽

Guilhem Cros ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Lymphocytes ◽

Immune Reconstitution ◽

Infectious Complications ◽

Post Transplant ◽

Cd8 T Lymphocytes ◽

Group 2 ◽

Hsc Transplantation ◽

Group 1

Abstract Abstract 4350 Introduction: Transplantation of T cell depleted (TCD) HSC transplantation has been associated with:1) an increased risk of infectious complications due to a very late immune reconstitution, 2) a non negligible risk of Graft Versus Host Disease (GVHD) requiring immunosuppressive therapy, and 3) an increased risk of graft rejection. It has been demonstrated that GVHD in murine models is mostly mediated by naïve T cells. Memory T cells have a reduced capacity to induce GVHD while preserving the anti-infectious capacity (Anderson BE et al., 2003). Removing CD45RA cells from donor lymphocytes could reduce infectious complications without induction of GVHD. This procedure was evaluated in two patients presenting multiple infections and treated with mismatch HSC transplantation. Methods: Post transplant immune reconstitution has been compared between two groups. Group 1: 7 patients (1 ostepetrosis, 1 Fanconi anemia and 5 Severe Combined Immuno Deficiency) transplanted with TCD HSC (age: 3 months-11 years, sex ratio F/M: 4/3). Group 2: 2 patients (1 ORAI1 deficiency and 1 MHC class II deficiency) transplanted with TCD HSC and CD45RA depleted cells of the CD34 negative fraction (age: 8 and 23 months, 1 female and 1 male). All patients had myeloablative conditioning regimen. CD34+ cell selection and CD45RA cell depletion procedures were performed using the Clini Macs system (Miltenyi Biotec). Group 1 received a median of 15.3 × 106CD34+ cells/kg with less than 5000 T lymphocytes/kg. Group 2 received respectively 8.8 and 12.3×106 CD34+ cells/kg with less than 5000 T lymphocytes/kg in HSC transplant and 0.9 and 9.2×106/kg CD45RO+ T cells. The thresholds of 100 CD4+ T lymphocytes and 50 CD8+ T lymphocytes per microliter at three months post transplantation, shown to allow sufficient protection against infectious complications (Hakki et al. 2003), were used in our analysis. Results: No significant difference in GVHD incidence was shown between the two groups since only 2/7 patients presented moderate GVHD in group 1 and no GHVD in group 2. Engrafment for both kind of pathology in group 2 was also remarkable Immune reconstitution of CD4+ and CD8+ T lymphocytes was earlier in group 2 as at one month we detected CD4+ T lymphocytes (430 and 24/μl) and CD8+ T lymphocytes (520 and 40/μl) respectively for patient 1 and 2. Whereas in group 1 no T lymphocytes were detected before two months post transplant. The number of CD4+ and CD8+ T lymphocytes at three months post transplantation was considerably increased in group 2 (CD4+: 609 and 190/μl; CD8+: 2088 and 95/μl) versus group 1 (CD4+: 14/μl; CD8+: 0.4/μl). Patient 1 in group 2 presented CMV reactivation at day 10 post transplant (87650 copies/ml, threshold 500) and was able to clear this infection at day 37 concomitantly to an increased CMV tetramer positive cells percentage (Tetramers at day 37/tetramers at day 10: 433 fold increase). Conclusion: The two patients treated with T-cell depleted haematopoietic stem cells (HSC) transplantation and add back of CD45RA negative DLI showed good engraftment, earlier and enhanced immune reconstitution without GVHD. Moreover, one patient developed specific and efficient anti-CMV response probably due to an expansion of the injected CD45RO T cells. These interesting preliminary results should be confirmed by a clinical trial. Disclosures: No relevant conflicts of interest to declare.

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