Influence of the HLA characteristics of Italian patients on donor search outcome in unrelated hematopoietic stem cell transplantation.

The information regarding the probability of finding a matched unrelated donor (MUD) within a relatively short time is crucial for the success of hematopoietic stem cell transplantation (HSCT), particularly in patients with malignancies. In this study, we retrospectively analyzed 315 Italian patients who started a search for a MUD, in order to assess the distribution of human leukocyte antigen (HLA) alleles and haplotypes in this population of patients and to evaluate the probability of finding a donor. Comparing two groups of patients based on whether or not a 10/10 HLA-matched donor was available, we found that patients who had a fully-matched MUD possessed at least one frequent haplotype more often than the others (45.6% vs 14.3%; P = 0.000003). In addition, analysis of data pertaining to the HLA class I alleles distribution showed that, in the first group of patients, less common alleles were under-represented (20.2% vs 40.0%; P = 0.006). Therefore, the presence of less frequent alleles represents a negative factor for the search for a potential compatible donor being successful, whereas the presence of one frequent haplotype represents a positive predictive factor. Antigenic differences between patient and donor observed at C and DQB1 loci, were mostly represented by particular B/C or DRB1/DQB1 allelic associations. Thus, having a particular B or DRB1 allele, linked to multiple C or DQB1 alleles, respectively, might be considered to be associated with a lower probability of a successful search. Taken together, these data may help determine in advance the probability of finding a suitable unrelated donor for an Italian patient.

High incidence of post-transplant cytomegalovirus reactivations in myeloma patients undergoing autologous stem cell transplantation after treatment with bortezomib-based regimens: a survey from the Rome transplant network.

The incidence of cytomegalovirus (CMV) reactivations in patients with multiple myeloma (MM) receiving autologous stem cell transplantation (ASCT) is relatively low. However, the recent increased use of novel agents, such as bortezomib and/or immunomodulators, before transplant, has led to an increasing incidence of Herpesviridae family virus infections. The aim of the study was to establish the incidence of post-engraftment symptomatic CMV reactivations in MM patients receiving ASCT, and to compare this incidence with that of patients treated with novel agents or with conventional chemotherapy before transplant. The study was a survey of 80 consecutive patients who underwent ASCT after treatment with novel agents (Group A). These patients were compared with a cohort of 89 patients treated with VAD regimen (vincristine, doxorubicin, and dexamethasone) before ASCT (Group B). Overall, 7 patients (4.1%) received an antiviral treatment for a symptomatic CMV reactivation and 1 died. The incidence of CMV reactivations was significantly higher in Group A than in Group B (7.5% vs. 1.1%; P = 0.048). When compared with Group B, the CMV reactivations observed in Group A were significantly more frequent in patients who received bortezomib, whether or not associated with immunomodulators (9.4% vs. 1.1%; P = 0.019), but not in those treated with immunomodulators only (3.7% vs. 1.1%; P = 0.396). These results suggest that MM patients treated with bortezomib-based regimens are at higher risk of developing a symptomatic CMV reactivation after ASCT.

3-Tesla MR spectroscopy in patients subjected to bone marrow transplantation: clinical correlations.

PURPOSE: This study evaluated the usefulness of 3-Tesla magnetic resonance (MR) spectroscopy in patients with non-Hodgkin's lymphoma (NHL) undergoing bone marrow transplantation (BMT). MATERIALS AND METHODS: Twelve NHL patients who were candidates for BMT underwent three MR examinations of the lumbosacral spine: before ablative therapy for BMT, 15±4 days and 54±24 days after BMT. The MR study was supplemented by spectroscopic analysis. The lipid content was calculated and expressed as a percentage of lipid signal intensity relative to total signal intensity [fat fraction (FF)]. RESULTS: In the first MR study, the FF was 62.5±7%, in the second it was 70.75±5% and in the third it was 75±1%. We observed a statistically significant difference between FF values calculated at the various MR studies (p=0.02) and between red blood cell count (p=0.017), platelet count (p=0.003) and haematocrit (p<0.001) at the three MR studies. FF had a statistically significant correlation with the number of circulating platelets (p<0.01) CONCLUSIONS: MR spectroscopy of the bone marrow of NHL patients undergoing BMT is noninvasive and highly sensitive for characterising and monitoring bone marrow after BMT.

Allogeneic hematopoietic stem cell transplantation for advanced mycosis fungoides and Sézary syndrome. An updated experience of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment option in advanced-stage mycosis fungoides (MF) and Sézary syndrome (SS). This study presents an updated analysis of the initial experience of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (EBMT) describing the outcomes after allo-HSCT for MF and SS, with special emphasis on the impact of the use of unrelated donors (URD). METHODS AND PATIENTS: Eligible for this study were patients with advanced-stage MF or SS who underwent a first allo-HSCT from matched HLA-identical related or URD between January/1997 and December/2011. Sixty patients have been previously reported. RESULTS: 113 patients were included [77 MF (68%)]; 61 (54%) were in complete or partial remission, 86 (76%) received reduced-intensity protocols and 44 (39%) an URD allo-HSCT. With a median follow up for surviving patients of 73 months, allo-HSCT resulted in an estimated overall survival (OS) of 38% at 5 years, and a progression-free survival (PFS) of 26% at 5 years. Multivariate analysis demonstrated that advanced-phase disease (complete remission/partial remission >3, primary refractory or relapse/progression in patients that had received 3 or more lines of systemic treatment prior to transplant or the number of treatment lines was not known), a short interval between diagnosis and transplant (<18 months) were independent adverse prognostic factors for PFS; advanced-phase disease and the use of URDs were independent adverse prognostic factors for OS. CONCLUSIONS: This extended series supports that allo-HSCT is able to effectively rescue over one third of the population of patients with advanced-stage MF/SS. High relapse rate is still the major cause of failure and needs to be improved with better strategies before and after transplant. The negative impact of URD is a matter of concern and needs to be further elucidated in future studies.

Acute Promyelocytic Leukemia: Update on the Mechanisms of Leukemogenesis, Resistance and on Innovative Treatment Strategies.

This review highlights new findings that have deepened our understanding of the mechanisms of leukemogenesis, therapy and resistance in acute promyelocytic leukemia (APL). Promyelocytic leukemia-retinoic acid receptor α (PML-RARa) sets the cellular landscape of acute promyelocytic leukemia (APL) by repressing the transcription of RARa target genes and disrupting PML-NBs. The RAR receptors control the homeostasis of tissue growth, modeling and regeneration, and PML-NBs are involved in self-renewal of normal and cancer stem cells, DNA damage response, senescence and stress response. The additional somatic mutations in APL mainly involve FLT3, WT1, NRAS, KRAS, ARID1B and ARID1A genes. The treatment outcomes in patients with newly diagnosed APL improved dramatically since the advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). ATRA activates the transcription of blocked genes and degrades PML-RARα, while ATO degrades PML-RARa by promoting apoptosis and has a pro-oxidant effect. The resistance to ATRA and ATO may derive from the mutations in the RARa ligand binding domain (LBD) and in the PML-B2 domain of PML-RARa, but such mutations cannot explain the majority of resistances experienced in the clinic, globally accounting for 5-10% of cases. Several studies are ongoing to unravel clonal evolution and resistance, suggesting the therapeutic potential of new retinoid molecules and combinatorial treatments of ATRA or ATO with different drugs acting through alternative mechanisms of action, which may lead to synergistic effects on growth control or the induction of apoptosis in APL cells.

HLA-identical sibling allogeneic peripheral blood stem cell transplantation with reduced intensity conditioning compared to autologous peripheral blood stem cell transplantation for elderly patients with de novo acute myeloid leukemia.

We conducted a retrospective registry-based analysis to compare the outcome of 361 allogeneic human leukocyte antigen (HLA)-identical peripheral blood stem cell transplants (PBSCT) with reduced intensity conditioning (RIC) to that of 1369 autologous (auto) PBSCT in patients aged 50 years or older with de novo acute myeloid leukemia (AML), performed from 1997 until 2003 and reported to the European Group for Blood and Marrow Transplantation. Median age was 58 and 57 years in the RIC and auto groups, respectively. RIC patients had more advanced disease at the time of transplant. At a median follow-up of 24 months for RIC and 16 months for auto, multivariate analysis showed a lower risk for relapse (RR 0.77, P=0.013) without increased non-relapse mortality (NRM) in RIC patients (RR 1.26, P=0.28). Moreover, leukemia-free survival (RR 1.22, P=0.02) and overall survival (OS) (RR 1.32, P=0.005) were superior in the RIC group. In patients in 1st (CR), fewer relapses were counterbalanced by significantly increased NRM. Therefore, there was no survival advantage in this subgroup. In patients in 2nd or subsequent CR, LFS and OS were superior in the RIC group. RIC transplants show encouraging results in this older patient population with de novo AML.

Hematopoietic stem cell transplantation for adults with acute promyelocytic leukemia in the ATRA era: a survey of the European Cooperative Group for Blood and Marrow Transplantation.

We performed a survey of the European Cooperative Group for Blood and Marrow Transplantation to analyze the outcome of 625 acute promyelocytic leukemia (APL) patients transplanted with auto- or allogeneic-hematopoietic stem cell transplantation (autoHSCT, alloHSCT) after 1993, in first (CR1) or in second complete remission (CR2). Leukemia-free survival (LFS) at 5 years in CR1 was 69% for 149 patients autografted and 68% for 144 patients allografted, whereas in CR2, LFS was 51% in 195 autoHSCT and 59% in 137 alloHSCT recipients, respectively. In the group of autoHSCT for CR1 (n=149), higher relapse incidence (RI) was associated with shorter time from diagnosis to transplant (<7.6 months); transplant-related mortality (TRM) was increased in older patients (>47 years), whereas for CR2, longer time from diagnosis to transplant (>18 months) was associated with increased LFS and decreased RI. In the alloHSCT group for CR1 (n=144), age (<33 years) was associated with increased LFS and decreased TRM and for CR2 (n=137), the use of mobilized peripheral blood stem cells was associated with decreased TRM. Female recipient, a female donor to male recipient and transplants performed before 1997 were associated with decreased RI. In conclusion, HSCT still appears to have a role in APL, especially for patients in CR2.

Identification of oral risk factors for chronic graft versus host disease in haematological patients who underwent allogeneic haematopoietic stem cell transplantation.

OBJECTIVE: The aim of this prospective observational study was to identify local risk factors for the development of clinical manifestations of oral chronic Graft versus Host Disease (cGvHD) in a cohort of patients affected by haematological malignant diseases who underwent allogeneic haematopoietic stem cell transplantation (HSCT). MATERIALS AND METHODS: In the context of an active collaboration between the Rome Transplant Network of the Hematology and the Oral Pathology Division at "Policlinico Tor Vergata", in Rome, 47 haematological patients were included in this trial based on a systematic dental screening and follow-up protocol. The dental checks were planned 1 month before the transplant procedure while the subsequent follow ups were scheduled on day +100, +180, +365 and + 730 after the transplant. The tool used for the dental checks was a detailed report including all the potential oral features responsible of mechanical, chemical or infective injuries, except for the drugs. RESULTS: Overall, 64% of patients (N=30) did not perform dental hygiene during the screening pre-transplant and 53% (25/47) developed cGvHD with oral involvement. The most part of patients (84%) who experienced oral manifestations of cGvHD during the follow-up period after HSCT did not perform dental hygiene before the transplant procedure. Moreover, the comparison between the "presence" or "absence" of dental hygiene before the allogeneic HSCT showed a statistical significant increasing during the follow-up period in the occurrence of oral lesions due to the cGvHD for patients who lack pre-transplant dental care (p=0.029).On the contrary, the frequency of the other factors such as malocclusions, fractured teeth, incongruous prosthesis, food, smoke, alcol and bad habits, resulted similar between the group with or without typical oral lesions of cGvHD. CONCLUSIONS: The prevention of oral infectious complications provided by primary and secondary dental cares can result in a great benefit for haematological patients who underwent allogeneic HSCT. The combined hematological and dental management represents a clinical need before and after allogeneic HSCT for the removal of inconvenient issues with impact on the short and long-term outcome. Poor dental hygiene seems to be a local risk factor for the development of oral lesions due to cGvHD. However, a larger cohort of patients is necessary to confirm these preliminary data and to evaluate the best preventive and therapeutic oral hygiene protocol in this specific setting.

Therapeutic efficiency of platelet gel for the treatment of oral ulcers related to chronic graft versus host disease after allogeneic haematopoietic stem cell transplantation.

BACKGROUND: Platelet (PLT) gel has been successfully used in tissue regeneration of diabetic and surgical wounds through the releasing of growth factors such as basic fibroblast and PLT-derived growth factors. Based on this background, our previous clinical trial have assessed the feasibility and efficacy of PLT gel for the treatment of muco-cutaneous lesions related to graft versus host disease (GvHD) after allogeneic haematopoietic stem cell transplantion (HSCT). The promising results reported in a small series of 6 patients, of whom 1 with oral ulcers, represent the rationale of the present study. MATERIALS AND METHODS: The aim of this study was to verify the efficacy and safety of PLT gel for treating oral ulcers due to chronic GvHD. Allogeneic hemocomponents were used to obtain PLT gel with an automated system for the on-site preparation and application of patient (autologous) or healthy blood donor (allogeneic)-derived fibrin sealant or PLT-rich fibrin (Vivostat system, Vivostat A/S). Ten patients with multiple oral lesions related to chronic GvHD underwent allogeneic PLT gel as local therapy alone or in combination with systemic therapy in half of the cases. RESULTS: After the second PLT gel application, all patients resumed the feeding and a significant improvement of the oral pain was observed. After a median of five PLT gel applications (range, 2-15), 7 out of 10 patients showed a complete response. No side effects were documented. CONCLUSION: These data confirm that the PLT gel may be used as a safe and effective tool, alone or in combination with systemic therapy, for the treatment of mucosal lesions of mouth related to cGvHD.

A comparison between allogeneic stem cell transplantation from unmanipulated haploidentical and unrelated donors in acute leukemia.

BACKGROUND: In the absence of a HLA-matched related or matched unrelated donor, allogeneic stem cell transplantation (allo-SCT) from mismatched unrelated donors or haploidentical donors are potential alternatives for patients with acute leukemia with an indication to allo-SCT. The objective of this study was to compare the outcome of allo-SCT from T cell-replete haploidentical (Haplo) versus matched (MUD 10/10) or mismatched unrelated donor at a single HLA-locus (MMUD 9/10) for patients with acute leukemia in remission. METHODS: Two hundred sixty-five adult patients with de novo acute leukemia in first or second remission that received a Haplo-SCT between January 2007 and December 2013 were compared with 2490 patients receiving a MUD 10/10 and 813 receiving a MMUD 9/10. Propensity score weighted analysis was conducted in order to control for disease risk imbalances between the groups. RESULTS: The weighted 3-year non-relapse mortality and relapse incidence were 29 and 30% for Haplo, 21 and 29% for MUD 10/10, and 29 and 25% for MMUD 9/10, respectively. The weighted 3-year leukemia-free survival (LFS) and overall survival (OS) were 41 and 46% for Haplo, 50 and 56% for MUD 10/10, and 46 and 48% for MMUD 9/10, respectively. Using weighted Cox model, both LFS and OS were significantly higher in transplants from MUD 10/10 compared from those in Haplo but not different between transplants from MMUD 9/10 and Haplo. The type of donor was not significantly associated with neither acute nor chronic graft-versus-host disease. CONCLUSIONS: Patients with acute leukemia in remission have better outcomes if transplanted from a MUD 10/10. We did not find any significant difference in outcome between transplants from MMUD 9/10 and Haplo, suggesting that both can be equally used in the absence of a 10/10 MUD. KEY POINT 1: Better outcomes using fully (10/10) matched unrelated donor for allo-SCT in acute leukemia in remission. KEY POINT 2: Similar outcomes after allo-SCT from unmanipulated haploidentical graft or mismatched (9/10) unrelated donor in acute leukemia in remission.

Recommendations for screening, monitoring, prevention, prophylaxis and therapy of hepatitis B virus reactivation in patients with haematologic malignancies and patients who underwent haematologic stem cell transplantation-a position paper.

SCOPE: Hepatitis B virus (HBV) infection reactivation is associated with high morbidity and mortality in patients with haematologic malignancy and/or haematopoietic stem cell transplantation (HSCT). However, information on this issue is limited. The scope of this position paper is to provide recommendations on HBV screening, monitoring, prophylaxis, treatment and vaccination in the patients described above. METHODS: These recommendations were developed from one meeting of experts attended by different Italian scientific societies as well as from a systematic literature review (of articles published through December 31, 2016) on HBV infection in haematologic patients and in patients who underwent haematopoietic stem cell transplantation published in the same issue of the journal. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess each recommendation's quality. QUESTIONS ADDRESSED: These recommendations provide the answers to the following questions: (a) HBV screening and monitoring: Who should be screened before chemotherapy? Which screening tests should be used? Should HBV-DNA detection be used to monitor HBV reactivation before starting antivirals? What is the best timeline to monitor HBV reactivation? (b) Prophylaxis in HBsAg-positive patients: Which antiviral drugs should be used to treat HBsAg-positive patients? How long should antiviral prophylaxis be provided to HBsAg-positive patients? (c) Prophylaxis in patients with resolved HBV infection: Which patients with resolved HBV infection should receive antiviral prophylaxis? Which antiviral drug should be used? How long should antiviral prophylaxis be provided? (d) HBV infection management strategy in autologous (auto-HSCT) and allogeneic HSCT (allo-HSCT): Which HSCT recipients should receive antiviral prophylaxis? Which antiviral drug should be used? How long should antiviral prophylaxis be provided? (e) Choice of antiviral drugs in the treatment of HBV reactivation: Should third-generation anti-HBV drugs be preferred to first- or second-generation antiviral drugs in the treatment of HBV reactivation with or without hepatitis flare in haematologic patients? (f) Immunization against HBV in patients with haematologic malignancies and/or patients who underwent HSCT: Should these patients be vaccinated? Which HBV vaccination schedule should be adopted? RECOMMENDATIONS: Haematologic patients should be screened for hepatitis B surface antigen (HBsAg) plus anti-hepatitis B core protein (HBc), and HBV DNA before chemotherapy. HBV DNA levels should be monitored monthly in all HBV-positive patients who do not receive prophylaxis. HBsAg-positive haematologic patients and those undergoing HSCT should receive third-generation antiviral therapy as prophylaxis. Anti-HBc-positive lymphoma patients and those receiving HSCT should receive antiviral prophylaxis. All HBV-negative haematologic patients should be vaccinated for HBV. The acquisition of data from well-designed studies is desirable in the near future.

Factors predicting outcome after allogeneic transplant in refractory acute myeloid leukemia: a retrospective analysis of Gruppo Italiano Trapianto di Midollo Osseo (GITMO).

The clinical outcome of primary refractory (PRF) AML patients is poor and only a minor proportion of patients is rescued by allogenic hematopoietic stem cell transplantation (HSCT). The identification of pre-HSCT variables may help to determine PRF AML patients who can most likely benefit from HSCT. We analyzed PRF AML patients transplanted between 1999 and 2012 from a sibling, unrelated donor or a cord blood unit. Overall, 227 patients from 26 Gruppo Italiano Trapianto di Midollo Osseo e Terapia cellulare centers were included in the analysis. At 3 years, the overall survival was 14%. By multivariate analysis, the number of chemotherapy cycles, (hazard ratio (HR): 1.87; 95% confidence interval (CI): 1.24-2.85; P=0.0028), the percentage of bone marrow or peripheral blood blasts (HR: 1.75; 95% CI: 1.16-2.64; P=0.0078), the adverse cytogenetic (HR: 1.44; 95% CI: 1.00-2.07; P=0.0508) and the age of patients (HR: 1.77; 95% CI: 1.08-2.88; P=0.0223) remained significantly associated with survival. Thus, we set up a new score predicting at 3 years after transplantation, an overall survival probability of 32% for patients with score 0 (no or 1 prognostic factor), 10% for patients with score 1 (2 prognostic factors) and 3% for patients with score 2 (3 or 4 prognostic factors).

Is there a stronger graft-versus-leukemia effect using HLA-haploidentical donors compared with HLA-identical siblings?

Haploidentical hematopoietic stem cell transplants (HSCTs) are increasingly used, but it is unknown whether they have a stronger graft-versus-leukemia (GVL) effect. We analyzed 10 679 acute leukemia patients who underwent HSCT from an HLA-matched sibling donor (MSD, n=9815) or a haploidentical donor (⩾2 HLA-antigen disparity, n=864) between 2007 and 2012, reported to the European Group for Blood and Marrow Transplantation. In a Cox regression model, acute and chronic graft-versus-host disease (GVHD) was added as time-dependent variables. There was no difference in probability of relapse between recipients of haploidentical and MSD grafts. Factors of importance for relapse after T-cell-replete grafts included remission status at HSCT, Karnofsky score ⩽80, acute GVHD of grade II or higher and chronic GVHD (P<10(-5)). Patients with post-transplant cyclophosphamide (n=194) had similar outcome as other T-cell-replete haploidentical transplants (n=369). Non-relapse mortality was significantly higher in the haploidentical group compared with that in MSD patients (P<10(-5)). Leukemia-free survival was superior in the MSD patients receiving T-cell-replete (P<10(-5)) or T-cell-depleted grafts (P=0.0006). The risk of relapse was the same in acute leukemia patients who received haploidentical donor grafts as in those given MSD transplants, suggesting a similar GVL effect.

Persistent risk of HBV reactivation despite extensive lamivudine prophylaxis in haematopoietic stem cell transplant recipients who are anti-HBc-positive or HBV-negative recipients with an anti-HBc-positive donor.

The overall rate of hepatitis B virus (HBV) reactivation was evaluated in a population of 373 haematological stem cell transplant (HSCT) patients treated with lamivudine (LMV) if they were anti-HBc-positive/HBV-DNA-negative recipients or if they were HBV-negative recipients with an anti-HBc-positive donor. The incidence of HBV reactivation was calculated in two groups of autologous (auto) or allogeneic (allo) HSCT patients who were stratified according to their HBV serostatus. The former group included 57 cases: 10 auto-HSCT and 27 allo-HSCT anti-HBc-positive recipients, two auto-HSCT and three allo-HSCT inactive carriers, and 15 allo-HSCT recipients with an anti-HBc-positive donor. Forty-seven (82.4%) patients in this group received LMV prophylaxis (the median (interquartile range, IQR) of LMV treatment was 30 (20-38) months). The second group consisted of 320 anti-HBc-negative auto-HSCT and allo-HSCT recipients with anti-HBc-negative donors. None of these patients received any prophylaxis. Two patients in the first group and two in the second group experienced reactivation of HBV infection, with an incidence of 3.5% (95% CI 0.4-12.1%) and 0.6% (95% CI 0.1-2.2%), respectively. Only one out of four reactivated patients was LMV-treated. The cumulative probability of HBV reactivation at 6 years from HSCT was 15.8% (95% CI 15.2-16.4%). Three of four viral isolates obtained from the HBV-reactivated patients harboured mutations in the immune-active HBsAg-region. In a HSCT population carefully evaluated for HBV prophylaxis, a risk of HBV reactivation persisted in the group of patients who were not LMV-treated. Only one LMV-treated patient experienced reactivation of HBV with a resistant HBV isolate.

Mitoxantrone, etoposide, and intermediate-dose cytarabine: an effective and tolerable regimen for the treatment of refractory acute myeloid leukemia.

Thirty-two patients with refractory acute myeloid leukemia (AML) received salvage therapy with a single course of mitoxantrone 6 mg/m2 intravenous (IV) bolus, etoposide 80 mg/m2 IV for a period of 1 hour, and cytarabine (Ara-C) 1 g/m2 IV for a period of 6 hours daily for 6 days (MEC). Eighteen patients were primarily resistant to conventional daunorubicin and Ara-C induction treatment; eight patients had relapsed within 6 months from initial remission; six patients had relapsed after a bone marrow transplantation (BMT) procedure. Overall, 21 patients (66%) achieved a complete remission (CR), two (6%) died of infection during induction, and nine (28%) had resistant disease. Age greater than 50 years was the only factor predictive for a significantly lower response rate (P = .03). The median remission duration was 16 weeks; the overall median survival was 36 weeks. Severe myelosuppression was observed in all patients resulting in fever or documented infections in 91% of patients. Nonhematologic toxicity was minimal. We conclude that the MEC regimen has significant antileukemic activity and acceptable toxicity in salvage AML. Its benefit in front-line AML therapy is being investigated.

Transplantation of peripheral blood stem cells as compared with bone marrow from HLA-identical siblings in adult patients with acute myeloid leukemia and acute lymphoblastic leukemia.

PURPOSE: Several studies show that allogeneic peripheral blood stem cells (PBSCs) engraft more rapidly than bone marrow (BM). However, the data are inconsistent with regard to acute and chronic graft-versus-host disease (GVHD), relapse, transplant-related mortality (TRM), and leukemia-free survival (LFS). PATIENTS AND METHODS: Between January 1994 and December 2000, 3,465 adult patients (older than 15 years of age) were reported to the European Group for Blood and Marrow Transplantation Registry from 224 centers. Among acute myeloid leukemia (AML) patients, 1,537 patients received BM and 757 patients received PBSC. In acute lymphoblastic leukemia (ALL) patients, the corresponding figures were 826 versus 345 patients who were analyzed for engraftment, GVHD, TRM, relapse, LFS, and survival. RESULTS: In multivariate analysis, the recovery of neutrophils and platelets was faster with PBSC than with BM (P <.0001). Chronic GVHD was associated with PBSC in patients with AML (relative risk [RR], 2.11; 95% confidence interval, 1.66 to 2.7; P <.0001) and ALL (RR, 1.56; 95% confidence interval, 1.09 to 2.27; P =.02). PBSC versus BM in patients with AML or ALL was not significantly associated with acute GVHD, TRM, relapse, survival, or LFS. In multivariate analysis of patients with AML, factors significantly associated with improved LFS included first remission at transplant (P <.0001), promyelocytic leukemia (M3) versus other French-American-British types (P <.0001), and donor age below median 37 years (P =.02). In patients with ALL, first remission (P <.0001) and methotrexate included in the immunosuppressive regimen (P =.001) were associated with improved LFS. CONCLUSION: Allogeneic PBSC results in faster neutrophil and platelet engraftment and a higher incidence of chronic GVHD than BM. However, acute GVHD, TRM, relapse, survival, and LFS were similar in patients receiving PBSCs versus BM.

Allogeneic stem cell transplantation for advanced acute promyelocytic leukemia: results in patients treated in second molecular remission or with molecularly persistent disease.

In all, 17 consecutive patients in hematological complete remission (HCR) of acute promyelocytic leukemia (APL) received allogeneic stem cell transplantation (SCT) from an HLA-identical sibling and were monitored by reverse transcriptase polymerase chain reaction of PML/RARalpha prior and after transplant. Median age was 31 years (range 3-50 years). At 10 years, the actuarial probabilities of nonrelapse mortality, relapse and disease-free survival were 32% (95% CI: 8-56%), 33% (95% CI: 6-60%) and 46% (95% CI: 22-70%). Six patients tested PCR +ve (1st HCR n=2; 2nd HCR n=3; 3rd HCR n=1) and 11 PCR -ve (2nd HCR n=11) pre-SCT. Of the six patients PCR +ve, two showed early persistence of PCR positivity and converted to sustained PCR negativity after CSA withdrawal (one died of secondary tumor in molecular remission and one is alive in relapse), while four converted to PCR -ve rapidly (one died of the underlying disease and three are in molecular remission). Of the 11 patients PCR -ve pre-SCT, six died (four of transplant-related mortality, one of relapse and one after heart transplantation) and five are alive, four in molecular remission and one is in relapse. Allogeneic SCT seems a valid option for advanced APL, particularly for the poor prognostic group of patients with pre-SCT molecularly persistent disease.

Adult Philadelphia-chromosome-positive acute lymphoblastic leukemia: experience of treatments during a ten-year period.

Adult Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph1-positive ALL) represents about 30% of all adult ALL, and is considered a poor prognosis disease, since complete remission (CR), which can be achieved in 50-70% of cases, is usually short in patients treated with conventional chemotherapy. Presently bone marrow transplantation, performed early in first CR is becoming the treatment of choice, as it has shown to be able to cure some cases. In a ten-year period, at our department, among 108 adult ALL patients, in which cytogenetics was successfully carried out at diagnosis, 24 (22%) resulted Ph1-positive. Molecular biology was performed in 13 out of these 24 patients: 10 patients showed a p210 rearrangement and three p190. All patients have been treated at induction with conventional drugs, with a CR rate of 96%. As post-remission therapy, the first 17 cases (group 1) followed a chemotherapeutic program, like the other adult ALL; while the remaining six patients (group 2) have been enrolled in a pilot study including early BM transplantation. In group 1, the median overall duration of first CR is 7 months; 50% of relapses were recorded within the first 6 months, although in this group five patients exhibited a first CR prolonged more than 30 months. In group 2, among the six patients, three were submitted to allogeneic bone marrow transplantation (BMT), and three to autologous bone marrow transplantation (ABMT). Overall median duration of first CR is 13 months. Three patients relapsed, three are in continuous CR for 11, 31 and 32 months.

Mitoxantrone, etoposide and intermediate-dose Ara-C (MEC): an effective regimen for poor risk acute myeloid leukemia.

A total of 74 patients with poor risk AML (median age 36.7 years, range 4.5-60.6) received a single course of a regimen including mitoxantrone (6 mg/m2 intravenous bolus daily, days 1 to 6), etoposide (80 mg/m2 intravenous over 1 h, daily, days 1 to 6) and intermediate-dose Ara-C (1 g/m2 over 6 h, daily days 1 to 6). 28 patients had failed initial remission induction with daunorubicin and conventional doses of Ara-C, 16 patients had secondary AML and 30 patients had relapsed from initial remission (five within six months, 15 over six months and ten after autologous or allogeneic bone marrow transplantation). Overall 41/74 patients (55%) achieved complete remission, 26 (35%) had resistant disease and seven (10%) died of infection during marrow hypoplasia. A 4-day course of the same regimen was given as consolidation to patients in complete remission. Subsequent antileukemic therapy was individualized. Profound myelosuppression and pancytopenia were universal resulting in fever or documented infections in almost 100% of patient; major hemorrhagic complications occurred in 39% of patients. Extrahematologic toxicity was mild to moderate consisting mostly of nausea and vomiting, oral mucositis and transient liver and cardiac dysfunction. We conclude that the MEC combination chemotherapy program seems to be an effective antileukemic regimen for secondary and advanced AML, with acceptable toxicity.

Idarubicin intensified BUCY2 regimen in allogeneic unmanipulated transplant for high-risk hematological malignancies.

Twenty-nine consecutive patients with high-risk hematological malignancy aged from 3 to 58 years underwent an unmanipulated graft from an HLA-identical sibling after an irradiation-free preparative regimen consisting of idarubicin (IDA), 21 mg/m2/day administered by continuous infusion on days -12 and -11, followed by busulphan (BU), 4 mg/kg/day orally from day -7 to -4, and cyclophosphamide (CY), 60 mg/kg/day intravenously on days -3 and -2 (IDA-BUCY2). Most clinically relevant extra-hematological regimen-related toxicities consisted of stomatitis observed in all subjects and hemorrhagic cystitis occurred in five cases (17%) within 100 days after transplant. Six patients (21%) developed a grade 2 acute graft-versus-host disease (GVHD) and three (10%) a grade 3 or 4; extensive chronic GVHD was assessed in nine of 22 (41%) evaluable patients. So far, 12 patients have died and 17 are alive, 16 of whom disease-free, 5-41 months after transplant (median, 15 months). The causes of death were related to GVHD in three patients, to sepsis in one and to disease recurrence in the remaining eight. At present, only one of nine relapsed patients is alive. For all patients the actuarial probability of survival (OS) at 1 and 2 years +/- standard error (s.e.) was 63 +/- 9% and 52 +/- 10%, respectively. The actuarial probabilities of disease-free survival (DFS), relapse and transplant-related mortality (TRM) at both 1 and 2 years +/- s.e. were 53 +/- 9%, 35 +/- 9% and 16 +/- 7%, respectively. These results are encouraging but not substantially different from those obtained in 28 patients with malignancy in advanced phase transplanted after the standard BUCY2 regimen, who had an actuarial probability of OS, DFS, relapse and TRM projected at 10 years +/- s.e. of 54 +/- 10%, 57 +/- 9%, 36 +/- 9% and 11 +/- 6%, respectively. Although the retrospective comparison between the two groups does not seem to show any advantage in the use of the IDA intensified regimen, only a prospective randomized trial could answer this question.