Is it appropriate to offer allogeneic hematopoietic stem cell transplantation to patients with primary refractory acute myeloid leukemia?

Although continued advances have been made in the treatment of acute myeloid leukemia (AML), approximately 20-30% of patients will never achieve a remission. For these patients with primary refractory AML, the only curative option remains an allogeneic stem cell transplant. Allogeneic transplantation provides the ability to administer myeloablative doses of chemotherapy or chemoradiotherapy, as well as the advantage of a possible graft-versus-leukemia effect. Difficulty in interpreting the literature is due to selection bias, in particular, the varying definitions of primary refractory disease with respect to the morphological criteria and the number of induction regimen required before being defined as being refractory. Regardless, it is a procedure with high treatment-related mortality and risk of relapse. Most studies demonstrate an event-free survival of 10-20% at 5 years. Predictive factors of outcome include blast cell count in the marrow, karyotype, the number of prior regimen, age, performance status and availability of a related donor. These prognostic factors should be considered prior to offering allogeneic transplantation for primary refractory AML. Those patients with many favorable prognostic factors and an HLA-matched related donor available would be the best candidate for the procedure. Those with many poor prognostic factors and only an unrelated donor available may be better served by being offered palliation or being enrolled in investigational studies.     

Peripheral blood stem cell transplantation as an alternative to autologous marrow transplantation in the treatment of acute myeloid leukemia?

The clinical use of autologous marrow transplantation in acute myeloid leukemia (AML) has been hampered by the inability to collect adequate numbers of cells after remission induction chemotherapy and the notably delayed hematopoietic regeneration following autograft reinfusion. Here we present a study in which the feasibility of mobilizing stem cells was investigated in newly diagnosed AML. Among 96 AML patients, 76 patients (79%) entered complete remission. Mobilization was undertaken with low dose and high dose schedules of G-CSF in 63 patients, and 54 patients (87%) were leukapheresed. A median of 2.0 x 10(6) CD34+ cells/kg (range 0.1-72.0) was obtained in a median of three leukaphereses following a low dose G-CSF schedule (150 microg/m2) during an average of 20 days. Higher dose regimens of G-CSF (450 microg/m2 and 600 microg/m2) given during an average of 11 days resulted in 28 patients in a yield of 3.6 x 10(6) CD34+ cells/kg (range 0-60.3) also obtained following three leukaphereses. The low dose and high dose schedules of G-CSF permitted the collection of 2 x 10(6) CD34-positive cells in 46% and 79% of cases respectively (P = 0.01). Twenty-eight patients were transplanted with a peripheral blood stem cell (PBSC) graft and hemopoietic repopulation was compared with the results of a previous study with autologous bone marrow. Recovery of granulocytes (>0.5 x 10(9)/l, 17 vs 37 days) and platelets (>20 x 10(9)/l; 26 vs 96 days) was significantly faster after peripheral stem cell transplantation compared to autologous bone marrow transplantation. These results demonstrate the feasibility of PBSCT in the majority of cases with AML and the potential advantage of this approach with respect to hemopoietic recovery.     

Allogeneic stem cell transplantation for mantle cell lymphoma—final report from the prospective trials of the East German Study Group Haematology/Oncology (OSHO)

This study was conducted in order to evaluate allogeneic stem cell transplantation (alloSCT) as consolidation for patients with mantle cell lymphoma (MCL). Patients with MCL were included into two prospective trials OSHO #060 (refractory/relapsed) and #074 (de novo). Induction was rituximab and chemotherapy. Responding patients proceeded to alloSCT. Minimal residual disease was monitored by quantitative RT-PCR detecting either t(11;14) or clonospecific CDR-III regions. In case of circulating lymphoma cells, immunomodulation (cyclosporine A withdrawal, rituximab, donor lymphocyte infusion) was initiated. Thirty-three of 39 patients underwent alloSCT after myeloablative (n?=?7) or toxicity-reduced (n?=?26) conditioning. Leukocytes engrafted at day +16 (median, range 0–101) and platelets at day +14 (0–142). Acute graft-versus-host disease stages I–II occurred in 42 % and stages III–IV in 15 %. Five patients have relapsed after SCT. The overall mortality after SCT was 24 % (n?=?8). Median follow-up after SCT was 2.8 years (range 0.0–10.9). Five-year progression-free survival was 67 %, and overall survival 73 % after SCT. The results were comparable for primary MCL and refractory/relapsed disease as well as for related vs. unrelated SCT. Younger patients had a significantly better outcome than the elderly. AlloSCT is a feasible and promising consolidation therapy for relapsed and refractory disease and an attractive option for young patients with de novo MCL of high risk.     

Long term follow-up of Asian patients with chronic myeloid leukemia (CML) receiving allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-identical sibling—evaluation of risks and benefits

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only known curative therapy for patients with chronic myeloid leukemia (CML), but is associated with significant morbidity and mortality. The recent introduction of imatinib mesylate (STI-571) and reduced intensity transplant regimens has made the choice of primary treatment for patients with CML increasingly difficult. We have evaluated the outcome of 53 patients who have received allogeneic HSCT from human leukocyte antigen (HLA)-identical sibling donors between October 1985 and March 2002, determined the variables affecting the outcome, and tried to define indications for this aggressive approach. Successful engraftment occurred in 49 (98%) of evaluable patients. Acute graft-versus-host disease (GVHD) of grade II to IV severity was observed in 63% of the evaluable patients whereas the incidence of chronic GVHD was 57.5%. The Kaplan-Meier estimate of survival at 10 years was 54% [95% confidence interval (CI): 38–70%] and 31% (95% CI: 6–56%) for patients with first chronic phase and more advanced diseases, respectively. Multivariate analysis showed that younger age, absence of grade III-IV GVHD, the use of busulphan and cyclophosphamide (BuCy) as preparative regimen, and transplantation performed after January 1992 were factors associated with improved survival. Patients who were 30 years of age or younger who had transplantation done within 1 year after diagnosis during their first chronic phase of disease had a particularly good prognosis, with a probability of surviving 10 years of 72% (95% CI: 52–92%). We conclude that allogeneic HSCT remains a feasible option for Asian patients with CML. The most favorable outcome is observed in younger patients with early phase of the disease.     

Repeated donor lymphocyte infusions overcome a myeloid sarcoma of the stomach resulting from a relapse of acute myeloid leukemia after allogeneic cell transplantation in long-term survival of more than 10 years

A patient with acute myeloid leukemia had a relapse with a myeloid sarcoma of the stomach 32?months after allogeneic bone marrow transplantation. The patient was treated with the first donor lymphocyte infusion (DLI) and one course of induction chemotherapy. Due to severe infectious complication after chemotherapy, the patient could not continue chemotherapy. Subsequently, the patient was treated with a total of 13 cycles of DLI at 1-2?month intervals. Complete remission was achieved and neither relapse nor graft versus host disease has occurred during a follow-up of more than 10?years.     

Targeting of the MNK–eIF4E axis in blast crisis chronic myeloid leukemia inhibits leukemia stem cell function

Chronic myeloid leukemia responds well to therapy targeting the oncogenic fusion protein BCR-ABL1 in chronic phase, but is resistant to treatment after it progresses to blast crisis (BC). BC is characterized by elevated β-catenin signaling in granulocyte macrophage progenitors (GMPs), which enables this population to function as leukemia stem cells (LSCs) and act as a reservoir for resistance. Because normal hematopoietic stem cells (HSCs) and LSCs depend on β-catenin signaling for self-renewal, strategies to specifically target BC will require identification of drugable factors capable of distinguishing between self-renewal in BC LSCs and normal HSCs. Here, we show that the MAP kinase interacting serine/threonine kinase (MNK)-eukaryotic translation initiation factor 4E (eIF4E) axis is overexpressed in BC GMPs but not normal HSCs, and that MNK kinase-dependent eIF4E phosphorylation at serine 209 activates β-catenin signaling in BC GMPs. Mechanistically, eIF4E overexpression and phosphorylation leads to increased β-catenin protein synthesis, whereas MNK-dependent eIF4E phosphorylation is required for nuclear translocation and activation of β-catenin. Accordingly, we found that a panel of small molecule MNK kinase inhibitors prevented eIF4E phosphorylation, β-catenin activation, and BC LSC function in vitro and in vivo. Our findings identify the MNK–eIF4E axis as a specific and critical regulator of BC self-renewal, and suggest that pharmacologic inhibition of the MNK kinases may be therapeutically useful in BC chronic myeloid leukemia.Chronic phase chronic myeloid leukemia (CML) is a myeloproliferative disorder that is characterized by the presence of the fusion gene BCR-ABL1 in primitive progenitors (1). BCR-ABL1 encodes a constitutively active tyrosine kinase that is causative for the condition (1), and, accordingly, therapeutic inhibition of BCR-ABL1 kinase elicits excellent responses in chronic phase (2). In contrast, myeloid blast crisis (BC) CML does not respond to BCR-ABL1 tyrosine kinase inhibitors (TKIs), suggesting that additional transforming events contribute to the BC phenotype (3). Several of these factors have recently been identified to be critical to BC pathogenesis, and include the acquisition of a β-catenin–driven self-renewal program in a committed progenitor population known as the granulocyte macrophage progenitor (GMP) (4, 5). BC GMPs are highly enriched for LSCs because they have the capacity to serially transplant immunodeficient mice (6). Importantly, the BC LSC population is also thought to underlie TKI resistance, as well act as a reservoir for the maintenance of the disease in patients (4, 6). That TKIs have minimal clinical activity in BC suggests that the LSC function in GMPs occurs independently of BCR-ABL1, a conclusion that is supported by the inability of BCR-ABL1 per se to confer LSC function on committed progenitors (7).In the present study, we set out to identify additional factors responsible for conferring stemness to the BC LSC population that might be drugable. We focused in particular on the cell’s translational machinery because our prior work had implicated cap-dependent mRNA translation in TKI resistance in CML (8–10), and because the process of mRNA translation encompasses a series of therapeutic targets that include several protein kinases (11). Specifically, we were interested in determining if there was a direct connection between the overexpression of the mRNA cap-binding protein and translation regulator eIF4E, which has been reported to be overexpressed in myeloid BC cells (12), and BC LSC function.eIF4E is essential for cap-dependent mRNA translation, which is the means by which the majority of mammalian mRNAs are translated (13). eIF4E recruits the translation initiation machinery to the 5′ cap of mRNAs so that initiation can proceed. This function of eIF4E is rate limiting, and represents a key regulatory node in the control of mRNA translation and protein expression (13, 14). Indeed, overexpression of eIF4E by itself has been shown to contribute directly to cellular transformation (15, 16), and, prognostically, eIF4E overexpression has also been shown to correlate with poorer outcome in a variety of human cancers (17). Mechanistically, the transforming properties of eIF4E have been linked to its ability to promote translation of genes involved in proliferation and survival (18, 19). Recent data have also highlighted the importance of eIF4E phosphorylation at serine 209 (S209) in transformation. These reports included the use of genetic approaches to demonstrate that nonphosphorylatable forms of eIF4E are less efficient in causing in vivo transformation, and also highlighted the therapeutic potential for targeting the MNK1/2 kinases, which phosphorylate eIF4E in vivo, as a way to prevent eIF4E-mediated transformation (15, 20, 21). Exactly how eIF4E phosphorylation contributes to cancer in these models is not entirely clear, although recent work has suggested that eIF4E phosphorylation may be particularly important for the translation of a subset of cancer-promoting mRNAs (15, 22). In the present work, we show that eIF4E is highly phosphorylated in BC GMPs, and that overexpression of eIF4E is sufficient to confer self-renewal function on bone marrow (BM) progenitors in a phosphorylation-dependent manner. Mechanistically, we show that the MNK–eIF4E axis activates Wnt/β-catenin signaling by increasing β-catenin mRNA translation and facilitating its nuclear translocation. Consistent with these findings, we demonstrate that a panel of MNK kinase inhibitors impairs the ability of BC GMPs to function as LSCs, including the capacity to serially transplant immunodeficient mice. The identification of a BC-specific MNK–eIF4E–β-catenin axis may therefore provide a therapeutic window for targeting LSCs without affecting normal HSC function.     

Pretransplant serum ferritin is associated with bloodstream infections within 100 days of allogeneic stem cell transplantation for myeloid malignancies

We retrospectively studied the association between iron overload and bloodstream infections (BSI) in the 100-day period following allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia or myelodysplastic syndromes. Serum ferritin was measured before transplantation to evaluate iron overload. Of 114 adult patients who underwent transplantation between 2000 and 2008, 36 (32%) developed BSI. Of the 44 isolates, 63% were Gram-positive bacteria, 32% were Gram-negative bacteria, and 4% were fungi. The median time to the onset of the first BSI was day 28 (range day 0-95) after transplantation. Univariate analysis revealed a significantly higher incidence of BSI in the high (≥ 1,000 ng/ml, n = 57) than in the low (< 1,000 ng/ml, n = 57) ferritin group (42.1 versus 21.1%, respectively, P = 0.017). Peripheral blood stem cell transplantation (PBSCT) (n = 23) showed a greater protective effect against BSI compared with bone marrow (n = 71) and cord blood (n = 20) transplantation. Pretransplantation serum ferritin (HR = 2.844, 95% CI: 1.180-6.859, P = 0.020) and PBSCT (HR = 0.135, 95% CI: 0.025-0.717, P = 0.019) were significant factors on multivariate analysis. In conclusion, pretransplantation serum ferritin significantly predicts BSI within the 100-day period after allo-HSCT.     

Busulfan-cyclophosphamide versus total body irradiation-cyclophosphamide as preparative regimen before allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia: what have we learned?

Most of the preparative regimens before allogeneic bone marrow transplantation include cyclophosphamide (Cy) with either busulfan (Bu) or total body irradiation (TBI). The Bu-Cy regimen has shown an advantage in chronic myeloid leukemia and TBI-Cy remains the standard conditioning regimen in acute lymphoblastic leukemia, but results are more conflicting in acute myeloid leukemia (AML). We report here the results of the most important studies comparing these two preparative regimens in AML. Survival is superior in all studies for patients treated with TBI and reached statistical significance in one of four trials. Two of three trials show significantly reduced transplant mortality and leukemia relapse. Higher incidences of veno-occlusive disease and hemorrhagic cystitis are reported with Bu. However, our long-term follow-up is limited, and to date no definitive conclusion can be drawn regarding late side effects. New approaches aiming at minimizing the toxicity without impairing the efficacy, such as targeted Bu plasma levels and nonmyeloablative conditioning regimens, seem promising but need to be evaluated further in future prospective studies.     

Sequence typing of human adenoviruses isolated from Polish patients subjected to allogeneic hematopoietic stem cell transplantation – a single center experience

ABSTRACT

Purpose: Human adenoviruses (HAdV) from species A, B and C are commonly recognized as pathogens causing severe morbidity and mortality in hematopoietic stem cell transplant (HSCT) recipients. The purpose of the present study was to determine HAdV types responsible for viremia in HSCT recipients at a large tertiary hospital in Poland.

Methods: Analysis of partial nucleotide sequences of HAdV hexon gene was used to type 40 clinical isolates of HAdV obtained from 40 HSCT recipients.

Results: We identified six different HAdV serotypes belonging to species B, C and E. We demonstrated high variability in sequences of detected HAdV types, and patients infected with the same HAdV types were not hospitalized at the same time, which suggests the low possibility of cross-infection. In almost all patients, anti-HAdV antibodies in IgG class were detected, which indicates a history of HAdV infection in the past. Clinical symptoms accompanying HAdV viremia were in 89%, and in 61.5% of individuals, HAdV was a sole pathogen detected. There were no cases with high-level HAdV viremia and severe systemic or organ infections. Graft-versus-host disease (GvHD) was present in patients infected with species B and C, but grade II of GvHD was observed only in patients infected with HAdV-B.

Conclusions: The predominance of HAdV-C and common presence of anti-HAdV antibodies in IgG class may strongly suggest that most infections in the present study were reactivations of HAdV persisting into the patient’s mucosa-associated lymphoid tissues. Variability of HAdV sequences suggests that cross-infections between patients were very rare.

ABBREVIATIONS: GvHD: graft-versus-host disease; HAdV: human adenoviruses; HSCT: hematopoietic stem cell transplantation     

Relapse of chronic myeloid leukemia after allogeneic stem cell transplantation: outcome and prognostic factors: the Chronic Myeloid Leukemia Subcommittee of the GETH (Grupo Español de Trasplante Hemopoyético)

In order to analyze the outcome of patients with chronic myeloid leukemia (CML) who relapse after allogeneic stem cell transplantation (SCT), we investigated data from 107 patients reported to the Spanish Registry, GETH. In all, 93 (87%) patients were treated after relapse; 36 out of 49 that failed to achieve a response received a second relapse-treatment, and seven a third one. At the last follow-up, the number of patients in molecular or cytogenetic remission was 29 and 13, respectively. Overall survival and progression-free survival after relapse were 53.6% (95% CI: 42.9--64.2) and 52% (95% CI: 41-63) at 5 years, respectively. In multivariate analysis, survival was significantly related to CML phase at relapse (cytogenetic or chronic phase vs advanced phases) and time from transplant to relapse (<1 vs >or=1 year). Patients with no adverse factors had a better survival compared with patients with one or two adverse features (65 vs 35 vs 0%, respectively). We conclude that a significant proportion of CML patients that relapse after transplantation can regain complete and long-lasting remissions with one or more salvage therapies. Disease stage at relapse and time from transplant to relapse should be taken into account when comparing results of different salvage treatments.     

Second line azacitidine for elderly or infirmed patients with acute myeloid leukemia (AML) not eligible for allogeneic hematopoietic cell transplantation—a retrospective national multicenter study

Elderly and infirm patients with acute myeloid leukemia (AML) with either induction refractory or relapse disease may benefit from treatment with azacitidine. We retrospectively reviewed the data from five tertiary centers in Israel, treated between 2009 and 2015. Thirty-four patients (median age 74 years) were identified. Sixty-two percent of the patients had relapsed disease and 38% had refractory disease. Median time of follow-up was 12.1 months. Out of a total of 327 courses, incidence of infectious episodes was 6%. Eighteen percent experienced major bleeding. Thirty-two percent of the patients achieved morphologic complete remission, and 26% had stabilization of disease during at least three courses. At 12 and 18 months after the first course of azacitidine, 33 and 10% of the patients were progression-free, respectively. Incidences of overall survival at 12 and 24 months were 54.5 and 16%, respectively. Age <75 years was associated with better overall survival. Normal leukocyte count at the first dose of azacitidine and standard doses of azacitidine were both associated with a better progression-free and overall survival. We conclude that azacitidine is feasible in patients who have failed induction chemotherapy and may be associated with prolongation of survival. A prospective trial to validate these results is warranted.     

Does younger donor age affect the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies beneficially?

Sixty three patients aged 27-66 years (median 52) were allografted from HLA-matched sibling (n=47), 10 of 10 allele-matched unrelated (n=19), or one-antigen/allele-mismatched (n=7) donors aged 24-69 years (median 46) after a conditioning regimen comprising 100 mg/m(2) melphalan. Cyclophosphamide (50 mg/kg) was also administered to patients who had not been autografted previously. Cyclosporine or tacrolimus, and mycophenolate mofetil were administered to prevent graft-versus-host disease (GVHD). The 2-year cumulative incidences of relapse and TRM were 55 and 24% respectively, and 2-year probabilities of overall survival (OS) and disease-free survival (DFS) were 36 and 21%, respectively. Poor performance status, donor age >45 years and elevated lactate dehydrogenase (LDH) increased the risk of treatment-related mortality (TRM), refractory disease and donor age >45 years increased the risk of relapse, and OS and DFS were adversely influenced by refractory disease, poor performance status, increased LDH, and donor age >45 years. Our data suggest that younger donor age is associated with better outcome after sub-myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) for hematologic malignancies due to lower TRM and relapse. This finding raises the question of whether a young 10-allele-matched unrelated donor is superior to an older matched sibling donor in patients where the clinical situation permits a choice between such donors.     

Treatment of relapsed AML and MDS after allogeneic stem cell transplantation with decitabine and DLI—a retrospective multicenter analysis on behalf of the German Cooperative Transplant Study Group

In contrast to the evidence regarding azacitidine (Aza), there is limited knowledge about the combination of decitabine (DAC) and donor lymphocyte infusions as salvage therapy for relapse after allogeneic stem cell transplantation (allo-SCT) so far. We retrospectively analyzed data of 36 patients with hematological (n?=?35) or molecular relapse (n?=?1) of acute myeloid leukemia (AML, n?=?29) or myelodysplastic syndrome (MDS, n?=?7) collected from 6 German transplant centers. Patients were treated with a median of 2 cycles DAC (range, 1 to 11). DAC was the first salvage therapy in 16 patients (44%), whereas 20 patients (56%) had previously received 1 to 5 lines of salvage therapy including 16 of them had been treated with Aza. In 22 patients (61%), a median of 2 DLI per patient (range, 1 to 5) was administered in addition to DAC. As a result, overall response rate was 25% including 6 complete remissions (CR, 17%) and 3 partial remissions (PR, 8%). Three patients within the first-line group achieved CR, while also 3 patients receiving DAC as second-line treatment reached CR including 2 patients with previous Aza failure. Median duration of CR was 10 months (range, 2 to 33) and no patient relapsed so far. The 2-year OS rate was 11% (±?6%) without any difference between first-line and pretreated patients. Incidence of acute and chronic graft-versus-host disease was 19 and 5%. Taken together, DAC exerts clinical efficacy in patients with AML or MDS relapsing after allo-SCT and is able to induce durable remissions in individual patients suggesting that DAC may be an alternative to Aza or even a second choice after Aza failure.     

Acute lung injury after allogeneic stem cell transplantation: is the lung a target of acute graft-versus-host disease?

Allogeneic hematopoietic stem cell transplantation (SCT) is an important therapeutic option for a number of malignant and nonmalignant conditions but the broader application of this treatment strategy is limited by several side effects. In particular, diffuse lung injury is a major complication of SCT that responds poorly to standard therapeutic approaches and significantly contributes to transplant-related morbidity and mortality. Historically, approximately 50% of all pneumonias seen after SCT have been secondary to infection, but the judicious use of broad-spectrum antimicrobial prophylaxis in recent years has tipped the balance of pulmonary complications from infectious to noninfectious causes. This mini review will discuss the definition, risk factors and pathogeneses of noninfectious lung injury that occurs early after allogeneic SCT.     

Effects of preemptive interferon-α monotherapy in acute leukemia patients with relapse tendency after allogeneic hematopoietic stem cell transplantation: a case-control study

Interferon-α (IFN-α) inhibits tumor growth and mimics graft-versus-leukemia after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the current case-control study, we compared treatment responses in acute leukemia patients with relapse tendency post-allo-HSCT receiving preemptive IFN-α after withdrawal of immunosuppressants (n?=?31) vs. receiving no IFN-α (n?=?67). In the IFN-α group, 25 patients responded to the treatment without progressing to hematological relapse. In the non-IFN-α group, only 22 patients responded to the treatment. The response rate differed significantly (80.6 vs. 32.8%, P <?0.001). The 2-year cumulative incidence of relapse was 31.6 and 61.2% in the IFN-α and the non-IFN groups, respectively (P?=?0.006). The 2-year leukemia-free survival and overall survival rate was 57.4 vs. 28.4% (P <?0.001) and 67.6 vs. 32.9% (P?=?0.001), respectively. Among the 31 patients in the IFN-α group, 18 patients (58.1%) developed graft-versus-host disease (GVHD): 6 acute and 12 limited chronic GVHD. Patients who developed GVHD had higher treatment response rate than patients without GVHD (88.9 vs. 53.8%, P?=?0.022). In conclusion, preemptive IFN-α therapy is a safe and effective treatment to prevent disease progression in high-risk patients with relapse tendency post-allo-HSCT.     

Second allogeneic haematopoietic stem cell transplantation in relapsed acute and chronic leukaemias for patients who underwent a first allogeneic bone marrow transplantation: a survey of the Société Française de Greffe de moelle (SFGM)

Although recurrent malignancy is the most frequent indication for second stem cell transplantation (2nd SCT), there are few reports that include sufficiently large numbers of patients to enable prognostic factor analysis. This retrospective study includes 150 patients who underwent a 2nd SCT for relapsed acute myeloblastic leukaemia (n = 61), acute lymphoblastic leukaemia (n = 47) or chronic myeloid leukaemia (n = 42) after a first allogeneic transplant (including 26 T-cell-depleted). The median interval between the first transplant and relapse, and between relapse and second transplant was 17 months and 5 months respectively. After the 2nd SCT, engraftment occurred in 93% of cases, 32% of patients developed acute graft-vs.-host disease (GVHD) >/= grade II and 38% chronic GVHD. The 5-year overall and disease-free survival were 32 +/- 8% and 30 +/- 8%, respectively, with a risk of relapse of 44 +/- 12% and a transplant-related mortality of 45 +/- 9%. In a multivariate analysis, five factors were associated with a better outcome after 2nd SCT: age < 16 years at second transplant; relapse occurring more than 12 months after the first transplant; transplantation from a female donor; absence of acute GVHD; and the occurrence of chronic GVHD. The best candidates for a second transplant are likely to be patients with acute leukaemia in remission before transplant, in whom the HLA-identical donor was female and who relapsed more than 1 year after the first transplant.     

Autologous peripheral blood stem cell transplantation in children with non-Hodgkin’s lymphoma: a report from the Korean society of pediatric hematology-oncology

Recent development of stratified chemotherapeutic regimens has rapidly improved the survival rate of non-Hodgkin’s lymphoma (NHL) of childhood. Despite these improvements, the outcome for children with recurrent or refractory NHL remains dismal. We explored the use of high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (HDC/PBSCT) for children with either refractory or recurrent NHL, and we evaluated various factors influencing outcome of HDC/PBSCT. Thirty-three patients underwent HDC/PBSCT in 11 institutes were enrolled. All patients had refractory or recurrent NHL. Sex, stage at diagnosis, histologic subtype (lymphoblastic, Burkitt’s, and large-cell lymphoma), LDH level at diagnosis, disease status at transplantation, and preparative regimens for HDC/PBSCT were explored. In regard to the patients, six had Burkitt’s lymphoma, 13 had lymphoblastic lymphoma, and 14 had large-cell lymphoma. The 2-year event-free survival (EFS) was 59.1±9.3%. The EFS for Burkitt’s, lymphoblastic, and large-cell lymphoma was 66.7±27.2, 50.5±14.8, and 82.1±11.7%, respectively. In comparison with lymphoblastic and non-lymphoblastic lymphoma, the relative risk for lymphoblastic lymphoma was higher than the others (P=0.037). EFS between anaplastic large-cell and diffuse large-cell lymphoma was 100 and 55.6±24.9%, respectively (P=0.106). Status at transplantation was the most predictive factor for the survival after HDC/PBSCT (EFS for CR 70.8±9.5% vs non-CR 20.0±17.9%, P=0.008). Transplantation-related complications were minimal, and infection was the most prevalent complication. HDC/PBSCT is considered applicable to recurrent or refractory pediatric NHL patients safely and it could replace conventional chemotherapy. In this study, children with CR status at the time of HDC/PBSCT showed higher survival rate. However, refractory or recurrent lymphoblastic lymphoma patients showed dismal results. Therefore, new therapeutic modalities may be needed for this group of NHL patients.An erratum to this article can be found at     

Low-dose alemtuzumab vs. standard policy for prevention of graft-versus-host disease in unrelated and related allogeneic stem cell transplantation—a matched pair analysis

Antibody-mediated in vivo T cell depletion is common prior to unrelated (URD) or mismatched allogeneic stem cell transplantation (alloSCT) and optional in HLA-identical sibling (FAM) alloSCT. While anti-thymocyte globulin (ATG) is the current standard, alemtuzumab is an alternative. The optimal dose of alemtuzumab has not been defined. This retrospective analysis compares low-dose alemtuzumab with ATG in URD alloSCT and with no antibody in FAM alloSCT. Twenty-eight patients treated with alemtuzumab (10 mg; HLA mismatch, 20 mg) were matched to 28 patients who have either received ATG (URD) or no antibody (noAB) according to disease, disease stage, age, transplant type and risk state. Both groups were compared for engraftment, outcome, disease-free (DFS) and overall survival (OS), graft-versus-host disease (GvHD), freedom from GvHD (ffGvHD) and transplant-related mortality (TRM). No significant differences were found between the groups for leukocyte engraftment, GvHD, ffGvHD, TRM, DFS and OS. There was a trend for reduction of cGvHD by alemtuzumab (p?=?0.05). A transplant-type stratified subanalysis consolidated equivalency of alemtuzumab and ATG in URD-SCT and indicates possible superiority of low-dose alemtuzumab compared to noAB in FAM-SCT. Low-dose alemtuzumab, as part of conditioning regimen prior to alloSCT, is safe and comparable to standard ATG. Prospective trials, particularly comparing alemtuzumab vs. noAB in FAM alloSCT, should be conducted.