Review for "Childhood survivors of high‐risk neuroblastoma show signs of immune recovery and not immunosenescence"

Abstract Background: Current SCT approaches consistently achieve rapid donor myeloid engraftment, but delayed immune recovery remains a significant obstacle and results in increased risk of infection and relapse. T cells are regenerated via 2 pathways, thymus-derived and peripheral expansion, processes for which IL-7 is critical. We postulated that non-myeloablative pre-transplant conditioning might preserve thymic function in pediatric SCT recipients thus enhancing thymus-derived naïve T cell regeneration. Methods: We analyzed T cell subsets, T cell receptor excision circles (TREC), and IL-7 levels in peripheral blood after SCT in 21 pediatric pts with high-risk malignancies (median age 14, range 4–21). Fludarabine-based induction chemotherapy was administered for disease control and targeted CD4 count reduction. Pre-transplant conditioning consisted of cyclophosphamide (1,200 mg/m2/day) and fludarabine (30 mg/m2/day) × 4 days plus melphalan (100 mg/m2 × 1 dose in sarcoma pts). Grafts consisted of G-CSF mobilized unmodified peripheral blood stem cells from 5–6/6 HLA-matched first-degree relatives (median CD34 dose 11.7 × 10E6/kg, range 4.4–19.1; median CD3 dose 416 × 10E6/kg, range 228–815). Cyclosporine was used for GVHD prophylaxis. Results: Donor-derived engraftment was rapid (absolute neutrophil count > 500/uL median day 9, range 8–11). Complete donor lymphoid chimerism (>95% by VNTR-PCR on CD3 sorted peripheral blood) was achieved in all by day 28. Immune recovery was brisk and sustained. Substantial numbers of naïve (CD45RA+/CD62L+) CD4+ and CD8+ T-cells were detected at day 28 (Fig 1). There was a steady increase in TREC from 3 to 12 months consistent with early, robust thymic-dependant T cell generation (Fig 2). This was not seen in adult pts treated on a parallel trial (data not shown). IL-7 levels were elevated and inversely correlated with T cell counts (r=−0.56, p<0.0001). Conclusions: Targeted immune depletion and NMSCT results in rapid, sustained immune reconstitution in pediatric pts with malignancy. Preserved thymic function appears to contribute to naïve T cell recovery in this setting. We postulate that non-myeloablative conditioning is thymus sparing and that this, in combination with immune depletion-induced IL-7 elevation, promotes early thymic-derived lymphoid recovery. This approach may serve as a strategy to overcome the prolonged immunodeficiency commonly encountered after allogeneic SCT in pediatrics and might be used as a platform to direct allogeneic anti-tumor immune responses in high-risk childhood cancers. Figure 1 Figure 1. Figure 2 Figure 2.

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Excellent Immune Recovery Following the Intensive Chemotherapy CODOX-M/IVAC, An Effective Therapy for HIV-Associated Burkitt’s Lymphoma (BL)

Blood ◽

10.1182/blood.v112.11.3612.3612 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3612-3612

Author(s):

Silvia Montoto ◽

Jamie Wilson ◽

Kate Shaw ◽

Maureen Heath ◽

Andy Wilson ◽

...

Keyword(s):

High Risk ◽

Disease Progression ◽

Stage Iii ◽

Concomitant Treatment ◽

Immune Recovery ◽

Intensive Chemotherapy ◽

End Of Treatment ◽

High Risk Disease ◽

Immunological Recovery

Abstract Background and aim: The outcome of patients with HIV-associated Burkitt’s lymphoma (HIV-BL) treated with infusional regimens remains poor, even in the highly active anti-retroviral (HAART) era. In contrast, promising results have been published in HIV-BL with the same intensive chemotherapies used in the non-HIV population. However, scarce data on immunological recovery following these regimens are available. The objective of this multicentre study was to analyse the outcome of patients with HIVBL treated with the intensive chemotherapy regimen CODOX-M/IVAC and HAART, with a particular emphasis on the analysis of immunological recovery after treatment. Patients and methods: 29 patients (22 male; median age: 38) from 3 UK centres consecutively treated with CODOX-M/IVAC from 2003 to 2008 were included in the study. CODOX-M/IVAC consisted of 2 alternating cycles of CODOX-M (cyclophosphamide 800mg/sqm day 1 and 200mg/sqm days 2–5, doxorubicin 40mg/sqm day 1, vincristine 1.5mg/sqm days 1 and 8, methotrexate 3g/sqm day 10) and IVAC (etoposide 60mg/sqm days 1–5, ifosfamide 1g/sqm days 1–5, cytarabine 1g/sqm bd days 1 and 2) for patients with high-risk disease and 3 cycles of CODOX-M for patients with low-risk disease. High-risk disease was defined by the presence of at least 2 of the following: stage III–IV, ECOG≥2, extranodal sites≥2 or high serum LDH. All patients received concomitant treatment with HAART (NRTI + NNRTI: 21; NRTI + PI: 8) and prophylactic antimicrobials as well as intrathecal prophylaxis and G-CSF as per protocol. Four patients received rituximab in combination with the chemotherapy. Lymphocyte subsets and plasma HIV-1 viral load (VL) were measured during chemotherapy and at 3-month intervals during follow-up. Results: HIV was diagnosed concomitantly with BL in 12 patients. The median CD4 count at BL diagnosis was 167/mm3 (range: 4–848), with CD4>200/mm3 in 41% of patients and VL being undetectable in 5 (18%) patients. Eight (28%) of the patients previously known to have HIV infection were on HAART before the diagnosis of BL. The majority of the patients (72%) had high-risk disease. Twenty patients (69%) were diagnosed in advanced stage (III–IV), with bone marrow (BM) involvement in 6 (21%) and central nervous system (CNS) infiltration in 5 (17%). The International Prognostic Index (IPI) was high (3–5) in 14 (48%) patients. Grade 3–4 non haematological toxicity was as follows: infection, 66% of the cycles; mucositis, 12%; and diarrhoea, 13%. Nine patients died during treatment, due to disease progression in 3 cases, toxicity in 5 (3 infections, 2 GI bleeding) and 1 patient died with a CNS lesion that was not biopsed. Response at the end of treatment amongst 23 assessable patients was as follows: complete response (CR)/CR uncertain (CRu): 16 patients (69%); partial response (PR): 4 (17%); progression: 3 patients (13%). After a median follow-up of 17 months (range: 9–67), 17 of 20 responding patients remain alive without disease progression, whilst 2 patients (1 CR, 1 PR) relapsed at 2 and 1 months after finishing treatment and died. One HAART non-compliant patient died in CR of HIV-related causes. Three patients in PR at the end of treatment survive without evidence of disease progression at 28, 37 and 51 months. Overall survival (OS) and disease-free survival (DFS) at 3 years were 49% and 70% respectively. Blood samples for immune recovery analyses were available for the majority of the patients during follow-up (81% 6 months after finishing chemotherapy, 86% at 12 and 24 months). VL was undetectable in 85% and CD4>200/mm3 in 53% of assessable patients 6 months after completing chemotherapy. Time (no. patients at risk) % CD4>200/mm 3 VL undetectable no./no. assessed % no./no. assessed % At BL diagnosis (29) 12/29 41 5/28 18 1 month after finishing chemotherapy (21) 5/17 29 10/15 67 6 months after finishing chemotherapy (16) 8/15 53 11/13 85 12 months after finishing chemotherapy (14) 9/12 75 10/12 83 Conclusions: This retrospective analysis demonstrates that the intensive regimen CODOX-M/IVAC is feasible and effective in HIV positive patients on HAART with BL. Immunological recovery after treatment, not previously reported after such intensive chemotherapy, is excellent. Whether concomitant treatment with rituximab will improve outcome warrants further study.

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Double Cord Blood Transplantation for Patients with High Risk Hematological Diseases: Delayed Immune Recovery and High Incidence of Infections.

Blood ◽

10.1182/blood.v108.11.2923.2923 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2923-2923 ◽

Cited By ~ 1

Author(s):

Vanderson Rocha ◽

Adrienne Madureira ◽

Marie Robin ◽

Marievonick Carmagnat ◽

Juliana F. Fernandes ◽

...

Keyword(s):

High Risk ◽

Cord Blood ◽

Nk Cells ◽

Cord Blood Transplantation ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Immune Recovery ◽

Blood Transplantation ◽

High Incidence

Abstract The possibility to perform double cord blood transplantation (dCBT) has extended its use in adults with high risk hematological disease; however there is no data on immune recovery and report on infections complications. We have performed a phase II study on 16 dCBT from 2004 to 2006. Ten patients had high risk malignant disorders (ALL=1, AML+MDS=6, CML=3) and 6 high risk of rejection (SAA=4, PNH=1 and Fanconi Anemia=1). Among those patients, 4 (25%) received a dBCT as a rescue of previous non-engrafted transplants (2 SAA, 1 AML and 1 CML). Analyses of T, B and NK cells phenotype were performed once a month during the first 3 months and ever two months until 12 months. The median age was 21 years (11–42), the median weight 63 kg (30–90) and the median follow-up was 6 months (3–18). Conditioning regimen varied according to disease (myeloablative) or second transplant (reduced intensity), all but two patients have received ATG. GVHD prophylaxis consisted in CsA + steroids in 12 patients and associated to MMF in 4. Results: 2 patients did not engraft (both with SAA), one patient relapsed 8 days after dCBT, and 12 patients engrafted at a median of 23 days (14–42). Chimerism available in 12 patients before day 100 showed both CB units in 7 patients. After day 100, in 8 evaluable patients, 3 patients had evidence of both CB units engraftement. Acute GVHD was observed in 5 patients (grade II in 4 and grade III in 1) and chronic GVHD in 7 out of 12 at risk. During the first 100 days, 9 CMV reactivations were diagnosed; 4 HSV (resistant to acyclovir); 3 HHV6 infections; 3 EBV reactivations; 2 adenovirus diseases, 4 VRS infections, 2 septicaemias, 3 fungal infections, 1 disseminated toxoplasmosis. After day 100, we observed 4 CMV reactivations, 1 CMV disease, 1 HSV, 1 adenovirus disease and 1 EBV-PTLD. Important lymphopenia was observed in all patients (median of 259mm3 at 3 months (n=14); 389 at 6 months (n=13) and 480 at 12 months (n=8). Median numbers of CD3/CD4 at 3, 6 and 12 months were: 8, 15 and 46 mm3 respectively; of NK cells 203, 249 and 115mm3, and of B cells were 0, 0 and 110 mm3, respectively. At 6 months overall survival was 58±14% and event-free survival was 52±14%. Six patients died: 2 of relapse and 4 from infections. Three out of 4 patients have been rescued of previous non-engraftment and are alive and well (4–18 months). In conclusion, despite the short follow-up dBCT seems to be an option to treat patients with high risk diseases and without a suitable compatible HLA donor. High incidence of infections and delayed immune recovery are major problems after dCBT.

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