Higher busulfan dose intensity does not improve outcomes of patients undergoing allogeneic haematopoietic cell transplantation following fludarabine, busulfan-based reduced toxicity conditioning

We evaluated the impact of busulfan dose intensity in patients undergoing reduced toxicity/intensity conditioning allogeneic transplantation in a multicenter retrospective study of 112 consecutive patients. Seventy‐five patients were conditioned with busulfan (0.8 mg/kg/dose IV × 8 doses), fludarabine (30 mg/m²/day, days ?7 to ?3), and 6 mg/kg of ATG [reduced intensity conditioning (RIC) group], while 37 patients received a more‐intense conditioning with busulfan (130 mg/m²/day IV, days ?6 to ?3), fludarabine (40 mg/m²/day, days ?6 to ?3) and 6 mg/kg of ATG [reduced toxicity conditioning (RTC) group]. At baseline both groups were matched for median age, unrelated donor allografts, and human leukocyte antigen‐mismatched allografts. More patients in RIC group had high‐risk disease, and higher median comorbidity index. There were no graft rejections. Median time to neutrophil (17 days vs. 15 days; p = 0.003) and platelet engraftment (16 days vs. 11 days; p < 0.001) was significantly longer in the RIC group. RTC group had significantly more bacterial (62.2% vs. 32%; p = 0.004) and fungal infections (13.5% vs. 1.3% p = 0.01). For RIC and RTC groups rates of grades II–IV acute GVHD (34% vs. 40%; p‐value = 0.54), and chronic GVHD (45% vs. 57%; p‐value = 0.30) were not significantly different. In similar order at 1 year the cumulative‐incidence of non‐relapse mortality (NRM; 12% vs. 21%; p‐value = 0.21) and relapse rates (38% vs. 39%; p = 0.96) were not significantly different. Patients in RIC and RTC groups had similar 1‐year overall survival (61% vs. 50%, p = 0.11) and progression‐free survival (50% vs. 36%, p‐value = 0.39). Our data suggest that the merits of higher busulfan dose intensity in the context of fludarabine/busulfan‐based RTC may be offset by higher early morbidity. Copyright © 2011 John Wiley & Sons, Ltd.     

Correlation of pretransplant and early post‐transplant response assessment with outcomes after reduced‐intensity allogeneic hematopoietic stem cell transplantation for non‐Hodgkin's lymphoma

BACKGROUND:

Chemotherapy sensitivity, defined simply as at least a partial response to chemotherapy, is an important outcome predictor for non‐Hodgkin lymphoma (NHL) patients undergoing reduced‐intensity allogeneic hematopoietic stem cell transplantation (allo‐HCT). The authors hypothesized that further differentiation of chemotherapy sensitivity by specific response, complete remission (CR) versus partial remission (PR) versus stable disease (SD) versus progression of disease (PD), correlates with post‐transplant outcomes.

METHODS:

The impact of pretransplant and early (28 days) post‐transplant disease response on transplant outcomes was analyzed in 63 NHL patients treated with reduced‐intensity allo‐HCT.

RESULTS:

The 3‐year event‐free survival (EFS) and overall survival (OS) (median potential follow‐up after reduced‐intensity allo‐HCT = 58 months) for all patients was 37% and 47%, respectively. The 3‐year EFS based on pretransplant response was: CR = 50%; PR = 66%; SD = 18%; no patient with PD pretransplant reached 3‐year follow‐up. The 3‐year OS based on pretransplant response was: CR = 63%; PR = 69%; SD = 45%. The 3‐year EFS based on post‐transplant response was: CR = 57%; PR = 32%; SD = 33%; no patient with PD post‐transplant reached 3‐year follow‐up. The 3‐year OS based on post‐transplant response was: CR = 65%; PR = 43%; SD = 50%. In multivariate analyses, pretransplant response was the best predictor of EFS (P < .0001). Pretransplant response (P < .0001) and age (P = .0035) were jointly associated with OS.

CONCLUSIONS:

These data suggest that NHL patients with pretransplant SD, generally considered inappropriate candidates, may benefit from reduced‐intensity allo‐HCT, and patients with pretransplant PD should only receive this therapy in clinical trials. Cancer 2010. © 2010 American Cancer Society.     

Durable remission with salvage second autotransplants in patients with multiple myeloma

BACKGROUND:

High‐dose chemotherapy with autologous hematopoietic cell transplant (auto‐HCT) has been shown to improve survival in patients with newly diagnosed multiple myeloma. However, the role of salvage auto‐HCT for relapsed patients, particularly in the era of novel therapeutics, is not well defined.

METHODS:

The authors performed a retrospective analysis of all 44 myeloma patients (24 men, 20 women) who received a second auto‐HCT as salvage between January 3, 1992 and November 4, 2008 at The University of Texas MD Anderson Cancer Center.

RESULTS:

Median interval between the first and salvage auto‐HCT was 30 months (range, 2‐78 months). Median age at salvage HCT was 54 years (range, 38‐73 years), and median number of salvage treatment regimens was 2 (range, 0‐5). Eleven (25%) patients had high‐risk chromosomal abnormalities on conventional cytogenetic studies between diagnosis and salvage auto‐HCT. Ten patients (23%) experienced grade 3 or higher nonhematologic toxicity after the salvage auto‐HCT. One patient died within 100 days, for a treatment‐related mortality of 2%. Best responses after salvage chemotherapy + salvage auto‐HCT were as follows: complete response (CR) + near CR, 11%; partial response, 79%; overall response rate, 90%. Eighteen (41%) patients received post auto‐HCT maintenance therapy. Median follow‐up from salvage HCT was 41 months. Kaplan‐Meier estimates of median progression‐free survival (PFS) and overall survival (OS) from time of salvage auto‐HCT were 12.3 and 31.7 months, respectively. Median OS from the time of diagnosis was 75 months. In a fitted Bayesian multivariate model, shorter time to progression after first auto‐HCT, greater number of prior therapies, African American race, and immunoglobulin G subtype were significantly associated with worse OS.

CONCLUSIONS:

In selected myeloma patients, a second auto‐HCT for salvage therapy is well tolerated, with acceptable toxicity. The overall response rate and PFS are comparable to other salvage regimens. Cancer 2012;3549–3555. © 2011 American Cancer Society.     

Graft vs. host disease and graft vs. myeloma effect after non-myeloablative allogeneic transplantation

For many years progress in event free and overall survival in patients diagnosed with multiple myeloma have been modest, however recently newer therapeutic options have become available and, for a small but increasing subset of patients, an “operational cure” can be offered. Although autologous transplantation is associated with a prolongation in event free and overall survival as compared to conventional chemotherapy, there is no plateau in the survival curves. By contrast, the use of allogeneic hematopoietic stem cells provides a tumor-free stem cell source and graft-vs.-myeloma activity leading to a higher frequency of long term survivors in molecular remission. Unfortunately, allogeneic transplantation has been associated with high transplant-related mortality (TRM). Non-myeloablative or reduced intensity conditioning (RIC) regimens, designed to be immunosuppressive rather than myeloablative, in an effort to reduce the toxicity and TRM associated with high dose chemotherapy, but maintaining the GVM effect, have been developed showing up to 90% overall response rate and low TRM. Interestingly, in a significant proportion of patients disease response is preceded by GVHD, suggesting a clear relationship between GVHD and graft vs. myeloma effect. Nevertheless these patients are at risk of developing life threatening complications and, on the contrary, some patients who reach disease control after GVHD and respond to GVHD therapy may finally relapse. Thus, efforts to separate GVM and GVHD are still required in order to improve the outcome of myeloma patients receiving allogeneic transplantation.     

Allogenic hematopoietic stem‐cell transplantation with reduced‐intensity conditioning in patients with refractory and recurrent multiple myeloma

BACKGROUND:

Allogeneic stem cell transplantation (SCT) with myeloablative conditioning is potentially curative therapy for myeloma, but is reportedly associated with a high risk of nonrecurrence mortality (NRM). Reduced‐intensity conditioning (RIC) allows for the reduction of NRM, but the recurrence rate is increased. The role and timing of allogeneic SCT in the disease course remains controversial. To the authors' knowledge, there are limited data regarding the long‐term outcome of RIC in the recurrent/refractory setting.

METHODS:

A retrospective analysis was conducted of SCT outcomes in 50 patients who received RIC for recurrent/refractory myeloma between the years 2001 and 2004. All patients were given fludarabine‐melphalan based conditioning and stem cell grafts from a related (n = 27) or unrelated donor (n = 23).

RESULTS:

The median age was 53 years. Forty‐seven patients failed a prior autologous SCT. Thirty patients were in disease remission at the time of SCT and 20 had stable or progressive disease. With a median follow‐up of 6.4 years (range, 5‐7.9 years), the overall and progression‐free survival (PFS) rates were 34% and 26%, respectively. The NRM rate was 26%. Adverse prognostic factors for survival included SCT not in remission, long duration of disease (>5 years from diagnosis), and transplantation from a female donor to a male recipient. The 7‐year PFS in 19 patients with none of these adverse prognostic factors was 47%. Chronic graft versus host disease and the achievement of complete remission after SCT were associated with improved outcome.

CONCLUSIONS:

Allogeneic SCT can result in long‐term PFS in a subset of myeloma patients who fail prior therapy and should be considered early after failure and after achieving remission. Cancer 2010. © 2010 American Cancer Society.     

Viewpoint: What is the role of allogeneic haematopoietic cell transplantation in the era of reduced-intensity conditioning--is there still an upper age limit? A focus on myeloid neoplasia.

Allogeneic haematopoietic cell transplantation (HCT) is the most effective curative therapy in acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Incidence of AML and MDS increases with age, peaking in the seventh decade. Despite improved Ara-C and anthracyclin-based chemotherapy regimens, the prognosis of AML in patients beyond 60 years of age is dismal. The introduction of peripheral blood-derived stem cell grafts into allogeneic HCT and the known anti-leukaemic effect of donor lymphocyte infusions paved the way for reduced-intensity conditioning (RIC) allogeneic stem-cell transplantation, which makes transplant in advanced age possible and significantly reduces transplant-related organ toxicity and mortality. The success of RIC HCT relies on the alloreactivity of the donor immune system and the graft-versus-leukaemia effect. We try to answer the following questions in this paper: who should receive RIC HCT? when and how should the transplant be performed? is there an upper age limit and what is the future of RIC HCT?     

Chronic graft-versus-host disease in the era of reduced-intensity conditioning.

In the past decade the field of hematopoietic stem cell transplantation has entered a new era with the introduction of reduced intensity conditioning (RIC) regimens. The impact of RIC on the incidence of chronic graft-versus-host disease (GVHD) has not been evaluated systematically. Factors confounding such analyses include short follow-up in studies, absence of prospective comparison trials, use of a variety of RIC regimens, lack of uniform GVHD prophylaxis and lack of rigorous criteria for the diagnosis and staging of chronic GVHD. This review discusses factors that appear to influence the incidence and clinical presentation of chronic GVHD in the RIC transplantation era. Overall, RIC seems to decrease the incidence and severity of acute GVHD through day 100 post-transplant when compared to conventional conditioning; however, there is little evidence to suggest that chronic GVHD is reduced after RIC. For the more definitive assessments of chronic GVHD after RIC it will be important to study this question in prospective comparison trials with long duration of follow-up. The recent National Institutes of Health chronic GVHD consensus project recommendations provide now the critically needed standardized guidelines for the diagnosis, classification and staging of chronic GVHD.     

Induction chemotherapy followed by allogeneic HCT versus upfront allogeneic HCT for advanced myelodysplastic syndrome: A propensity score matched analysis

To reduce post‐transplant relapse, acute myeloid leukemia (AML) type remission induction chemotherapy has been attempted to reduce disease burden before allogeneic hematopoietic cell transplantation (HCT) in patients with advanced myelodysplastic syndrome (MDS). However, the efficacy of induction chemotherapy before HCT is unclear. We retrospectively analyzed the Japanese registration data of 605 adult patients, who had received allogeneic HCT for advanced MDS between 2001 and 2016, to compare the post‐transplant relapse between patients who received induction chemotherapy followed by allogeneic HCT and those who received upfront HCT. Propensity score matching identified 230 patients from each cohort. There were no significant differences in overall survival and non‐relapse mortality between the two groups. The cumulative incidence of relapse was significantly higher in patients who received induction chemotherapy than those who received upfront HCT. In the subgroup analyses, upfront HCT had a significantly reduced relapse incidence among patients with poor cytogenetics, those with higher international prognostic scoring system at diagnosis, and those who received reduced‐intensity conditioning. Our results suggested that AML type remission induction chemotherapy before HCT did not improve post‐transplant relapse and survival for adult patients with advanced MDS. Upfront HCT is preferable for patients with a poor karyotype.     

Allogeneic hematopoietic stem cell transplant with reduced-intensity conditioning for chronic lymphocytic leukemia in Sweden: does donor T-cell engraftment 3 months after transplant predict survival?

Thirty-eight adult patients with chronic lymphocytic leukemia (CLL) underwent reduced-intensity conditioning (RIC) allogeneic stem cell transplant (allo-SCT) in Sweden between 1999 and 2007. The cumulative incidences of acute graft-versus-host disease (GVHD) grades II-IV and chronic GVHD were 29% and 47%, respectively. Rates of non-relapse mortality, progression-free survival (PFS) and overall survival (OS) were 18%, 47% and 74% at 1 year, and 21%, 25% and 45% at 5 years, respectively. T-cell chimerism after transplant was measured in 31 out of 34 patients (91%) surviving beyond day +100. Seventeen patients achieved >90% donor T-cell engraftment at 3 months after allo-SCT and, compared with the 12 patients with ≤90% donor T-cell engraftment, they showed favorable PFS at 1 year (82% vs. 33%, p =0.002) and better long-term PFS and OS (p =0.002 and 0.046, respectively). Donor T-cell engraftment of >90% at 3 months after RIC allo-SCT for CLL seems to predict favorable short-term and long-term outcome.     

异基因造血干细胞移植治疗多发性骨髓瘤研究进展

异基因造血干细胞移植（allo-HSCT）是唯一可能治愈多发性骨髓瘤（MM）的方法,但较高的移植相关死亡（TRM）率限制了其应用。尽管减低强度预处理（RIC）的allo-HSCT降低了TRM率,但其疗效仍不优于自体造血干细胞移植（auto—HSCT）。因此需要进一步研究降低移植毒性和促进移植物抗骨髓瘤（GVM）效应的新策略,以便使RIC allo-HSCT更加安全有效。文章对目前allo—HSCT在MM中的研究进展进行了综述。     

Pre-transplant consolidation chemotherapy may not improve outcomes after reduced intensity conditioning hematopoietic stem cell transplantation for acute myeloid leukemia in first complete remission

The role consolidation chemotherapy prior to reduced-intensity (RIC) HCT is unclear. We reviewed 60 consecutive patients with AML in CR1 undergoing RIC HCT at the University of Minnesota and evaluated outcomes based on exposure to pre-transplant consolidation chemotherapy. The two year incidence of relapse and the probability of overall survival were similar between those who did and did not receive consolidation chemotherapy. The 2 year incidence of transplant-related mortality was slightly higher in those who did not receive consolidation and correlated with a higher HCT comorbidity index (HCT-CI) in that cohort. Our data suggest that exposure to consolidation chemotherapy prior to RIC HCT may not improve post-transplant outcomes for patients with AML in CR1.     

Predictors of oral mucositis in patients receiving hematopoietic cell transplants for chronic myelogenous leukemia.

PURPOSE: Oral mucositis is a nearly universal and often severe complication following hematopoietic cell transplantation (HCT). The objective of this study was to evaluate factors predicting oral mucositis severity among 133 patients undergoing allogeneic HCT for chronic myelogenous leukemia. PATIENTS AND METHODS: All patients were transplanted between 1992 and 1999, were >or= 18 years of age, received either cyclophosphamide/total-body irradiation (TBI) or busulfan/cyclophosphamide conditioning regimens, and received four doses of methotrexate for graft-versus-host disease prophylaxis post-transplant. Oral mucositis was measured by a trained examiner every 2 to 3 days using the Oral Mucositis Index (OMI). Multiple linear regression analysis was used to identify predictors of mean OMI during days 6 to 12, 1 to 18, and the maximum OMI score between days 1 to 18. RESULTS: TBI containing conditioning regimens, body mass index >or= 25, and methylenetetrahydrofolate reductase 677 TT genotype were found to be predictive of higher mean OMI scores (P <.05). Pretransplant multivitamin supplement use was associated with lower mean OMI scores compared to those who did not use supplements. Smoking status, race, pretransplant treatment with interferon-alfa or hydroxyurea, and patient/donor ABO compatibility were not associated with mean OMI scores. CONCLUSION: Patients who are scheduled to receive conditioning regimens containing TBI, have a pretransplant body mass index >or= 25, or carry the methylenetetrahydrofolate reductase 677 TT genotype should be considered at greater risk of developing oral mucositis following HCT. Future studies should investigate whether multivitamin supplementation before HCT could reduce mucositis severity.     

Allogeneic stem cell transplantation using lymphoablative rather than myeloablative conditioning regimen for relapsed or refractory lymphomas

In relapsed or refractory non‐Hodgkin lymphoma (NHL), allogeneic hematopoietic stem cell transplantation (allo‐HSCT) provides graft‐versus‐lymphoma activity resulting in fewer incidences of relapse. However, therapy‐related mortality (TRM) remains an important challenge. We attempted to introduce our reduced‐intensity conditioning (RIC) regimen. From 2007 to 2013, we treated 28 relapsed or refractory NHLs with allo‐HSCT. All were pre‐conditioned with fludarabine [FLU, 180 mg/body surface area (BSA)/6 days] and melphalan (MEL, 70 mg/BSA/1 day); 25 (all but 3) were additionally treated with total body irradiation (TBI, 800 cGy/4Fx/2 days). Peripheral blood stem cells were collected from matched siblings (n = 10) or suitably matched unrelated (n = 18) donors. There were eight diffuse large B‐cell lymphomas, seven peripheral T‐cell lymphoma not otherwise specified, give lymphoblastic lymphomas, two mantle cell lymphomas, and six various other lymphomas. Of these patients, 10 relapsed after auto‐HSCT, 5 relapsed after chemotherapy, and 13 were refractory lymphomas. After allo‐HSCT, complete remission was achieved in 22 (78.5%) patients. After a median follow‐up of 24.8 months, 3‐year overall survival and disease‐free survival were 62.4 and 59.2% and the 3‐year TRM and relapse incidence were 14.9 and 28.6% respectively. Acute and chronic graft‐versus‐host diseases (GVHDs) were identified in 17 (≥Grade II in 12 patients) and 18 patients respectively, and the group with chronic GVHD showed favourable survival outcomes. In relapsed or refractory NHL, RIC‐allo‐HSCT using FLU + MEL + 800 cGy TBI showed favourable survival outcomes with acceptable TRM and relapse incidence. Copyright © 2015 John Wiley & Sons, Ltd.     

Donor Lymphocyte Infusions After Allogeneic Transplantation: A Single-Center Experience

Allogeneic hematopoietic cell transplantation (AHCT) represents the only curative therapy for many hematological malignancies. The graft versus leukemia effect, driven by donor T cells, plays a major role in its curative potential. This effect is sometimes very evident when patients with acute myeloid leukemia and myelodysplasia relapse after AHCT and are treated with donor lymphocyte infusions (DLIs). We retrospectively reviewed the charts of 64 patients who received DLI between 2012 and 2017 in our center. The mean age of the patients was 59 years (range, 34-79). Fifty percent were male (n = 32). The mean follow-up time after AHCT was 50.17 months (range, 8-174). The indication for DLI were disease progression, mixed chimerism, minimal residual disease, and other etiologies in 43.8%, 40.7%, 14%, and 1.5% of patients, respectively. The most common diagnosis was acute leukemia, followed by multiple myeloma. Of all patients, 59.4% received a transplant from a related donor, 39% received a transplant from an unrelated donor, and 1.6% received a transplant from a haploidentical donor. Reduced-intensity conditioning AHCT was the most frequent regimen used (53%). DLI was given alone in 79.7% of patients. Prophylactic DLI was given at 30 days after transplantation in patients who received human leukocyte antigen (HLA)-matched related human stem cell transplantation (HSCT) or 45 to 60 days post-transplant in patients receiving haploidentical HSCT or HLA-matched unrelated HSCT. Patients were treated without graft versus host disease (GVHD) prophylaxis. The use of DLI after transplantation remains a feasible procedure with rates of response >60%. Moreover, DLIs are well tolerated with a GVHD rate <10% in our series. We can hypothesize that in our experience the efficacy of this strategy does not rely on the induction of GVHD.     

Targeting complete response with upfront bortezomib consolidation versus observation after the achievement of complete response following autologous transplantation for multiple myeloma (TUBA study)

Complete response (CR) after treatment for multiple myeloma is associated with superior progression‐free survival (PFS). Multiple myeloma patients were prospectively recruited for induction treatment with bortezomib and dexamethasone (BD) followed by autologous hematopoietic cell transplantation (auto‐HCT) between 2010 and 2012. If patients did not achieve CR after auto‐HCT, BD consolidation therapy was added to target CR. After the BD induction phase (n = 46), greater than or equal to CR was achieved in 4 patients (8%). After auto‐HCT (n = 34), greater than or equal to CR was achieved in 9 patients (20%) and very good partial response (VGPR) was achieved in 11 (24%). Of the 24 patients who received auto‐HCT and whose response was less than CR, 21 received BD consolidation therapy for a median of 4 courses. Finally, the maximum response with or without BD consolidation was greater than or equal to CR in 19 (41%), VGPR in 7 (15%), and PR in 6 (13%). Through BD consolidation, CR was achieved in 8 of 11 patients with post‐HCT VGPR and in 2 of 12 patients with post‐HCT PR. In total, 4 year PFS and overall survival were 43 and 80%, respectively. After adjusting for clinical factors, there was no difference in PFS between CR patients after auto‐HCT and BD consolidation, while patients with less than or equal to VGPR after consolidation had a significantly lower PFS. Patients with post‐HCT CR showed good PFS, and targeting CR through BD consolidation could improve the CR rate. It would be worthwhile to prospectively compare the efficacy of consolidation only for patients who failed to achieve CR to a universal consolidation strategy.     

Combination of anti‐CD4 antibody treatment and donor lymphocyte infusion ameliorates graft‐versus‐host disease while preserving graft‐versus‐tumor effects in murine allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is not only a well‐established immunotherapy for hematologic malignancies, but is potentially useful for treating solid tumors refractory to available therapies. However, application of allo‐HSCT to solid tumors is limited, despite the beneficial antitumor effects, by the risk of graft‐versus‐host disease (GVHD). CD4⁺ T cells have been implicated in several aspects of GVHD, and suppress antitumor CD8⁺ T‐cell responses. In the present study, we investigated clinically applicable allo‐HSCT protocols designed to maximize antitumor effects while reducing the risk of GVHD. We used a mouse model of allo‐HSCT with s.c. tumors. We found that myeloablative conditioning was associated with better inhibition of tumor growth but with severe acute GVHD. Early treatment with anti‐CD4 mAb substantially ameliorated GVHD while preserving antitumor effects, leading to improved survival in myeloablative allo‐HSCT. Late treatment with anti‐CD4 mAb also ameliorated GVHD to some extent. Donor lymphocyte infusion in GVHD mice treated with anti‐CD4 mAb further suppressed tumor growth without exacerbating GVHD. Collectively, our results suggest that myeloablative allo‐HSCT followed by anti‐CD4 mAb treatment and donor lymphocyte infusion could be a potent and safe immunotherapy for patients with cancers refractory to available therapies.     

造血干细胞移植治疗多发性骨髓瘤

 自体造血干细胞移植（auto-HSCT）显著提高了65岁以下多发性骨髓瘤（MM）患者的疗效,早期进行auto-HSCT已成为年轻初发MM患者的标准治疗方法。美法仑200 mg／m2目前仍被认为是最佳的预处理方案。对于首次自体移植后未达到非常好的部分缓解（VGPR）及以上疗效的患者,推荐采用序贯双次auto-HSCT以进一步提高疗效。新的治疗MM药物在auto-HSCT前和预处理中的应用可提高自体干细胞移植（ASCT）疗效。异基因造血干细胞移植（allo-HSCT）虽然 完全缓解（CR）率较高,但因具有较高的移植相关毒性,患者的长期生存率并不比ASCT高。减低剂量的allo-HSCT由于预处理毒性小,移植相关死亡率低,将可能成为一种安全有效的治疗方法。ASCT结合非清髓的allo-HSCT的疗效目前还需大样本的研究来证实。     

Efficacy and Safety of Busulfan‐Based Conditioning Regimens for Multiple Myeloma

Multiple myeloma is a malignancy of B cells characterized by accumulation of abnormal plasma cells in the bone marrow. In the past 20 years, the use of high‐dose therapies and novel agents has resulted in significant and meaningful improvements in survival. Autologous stem cell transplantation (auto‐SCT) following a high‐dose melphalan‐conditioning regimen represents the standard of care for younger patients as well as older patients with a good performance status. A number of strategies have been proposed to improve the outcome of auto‐SCTs, including the incorporation of new agents such as thalidomide, lenalidomide, and bortezomib into the induction regimen administered before auto‐SCT; the administration of maintenance therapy after auto‐SCT; the incorporation of novel agents into chemotherapeutic regimens after transplantation as consolidation therapy; and the use of reduced‐intensity allogeneic transplantation after an initial autograft. Although these approaches have demonstrated some success in improving responses after auto‐SCT, none of these strategies are curative. An additional strategy to improve outcomes after auto‐SCT is to enhance the immediate pretransplant conditioning regimens by either increasing the dose of melphalan or by incorporating novel agents, such as busulfan. This literature review focuses on the efficacy and safety of busulfan‐based conditioning regimens for auto‐SCT in patients with multiple myeloma.     

Chimerism and minimal residual disease monitoring after reduced intensity conditioning (RIC) allogeneic transplantation.

Since graft-versus-leukemia (GVL) is the main weapon for disease eradication after reduced intensity conditioning (RIC) allogeneic SCT, the availability of sensitive and specific techniques to monitor changes in tumor load after transplant are especially helpful. These minimal residual disease techniques would allow an early intervention in the event of low tumor burden, for which immunotherapy is highly effective. Some authors have found an association between persistence of MRD, mixed chimerism and risk of relapse. Nevertheless, data from the literature remain contradictory and further correlations should be established, especially in RIC transplants. In this study we have analyzed the impact of MRD and chimerism monitoring on the outcome of 34 patients undergoing RIC allogeneic SCT who were considered poor candidates for conventional transplantation due to advanced age or other concurrent medical conditions. At day +100 25 (75%) patients reached complete remission (CR), there were five (15%) partial responses and three patients progressed. Incidence of grade 2-4 aGVHD and extensive cGVHD were 35% and 58%, respectively. Sixteen percent of patients developing aGVHD relapsed as compared to 47% in those without aGVHD (P = 0.03) and also 10% of patients developing cGVHD relapsed as compared to 50% relapses in those without cGHVD (P = 0.03). Four patients (12%) died due to early (n = 1) and late (n = 3) transplant-related mortality. After a median follow-up of 15 months, 24 out of the 34 patients remain alive. Projected overall survival and disease-free survival at 3 years are 68% and 63%, respectively. Early chimerism analysis showed 67% of patients with complete chimerism (CC) in bone marrow (BM), 86% in peripheral blood (PB), 89% in granulocytes and 68% in T lymphocytes. On day +100, these figures were 68%, 79%, 90% and 73%, respectively, and on day +180 there were 83% patients with CC in BM, 100% in PB, 100% in granulocytes and 100% in T lymphocytes. We observed a trend to a higher incidence of relapse in patients with mixed chimerism (MC) as compared to patients with CC. MRD monitoring by flow cytometry and/or RT-PCR analysis was performed in 23 patients. MRD assessment on days +21 to +56 after transplant allowed identification of patients at risk of relapse. In this sense, seven out of 12 patients (58.3%) who had positive MRD on days +21 to +56 relapsed as compared to none out of 11 patients who had negative MRD (P = 0.002). Of the seven patients with criteria to monitor MRD who relapsed after transplant, all but one remained MRD positive until relapse. By contrast, 10 patients remained MRD negative and all of them are in continuous CR. In nine additional patients, persistence of MRD or mixed chimerism was observed after transplant and withdrawal of cyclosporin with or without DLI was performed. Only two out of these nine patients relapsed. MRD clearance was preceded by CC and GVHD. In conclusion, in our study we found that RIC allogeneic transplantation can be used in patients considered poor candidates for conventional transplantation due to advanced age or other concurrent medical conditions with both low toxicity and low transplant-related mortality. Simultaneous studies of both chimerism and MRD are a useful tool in order to predict risk of relapse in patients undergoing RIC transplants and so can be helpful for individualizing treatment strategies after transplant.     

Pretransplant model for end stage liver disease score predicts posttransplant incidence of fungal infections after liver transplantation

Liver transplant recipients are at a significant risk for invasive fungal infections (IFI). This retrospective study evaluated the impact of the pretransplant model for end stage liver disease (MELD) on the incidence of posttransplant IFI in a single centre. From 2004 to 2008, 385 liver transplantations were included, from which 210 transplantations were conducted allocated by Child Turcotte Pugh and 175 were allocated by MELD score. Both groups differed regarding the age of transplant recipients (50.1 ± 10.7 vs. 52.5 ± 9.9, P = 0.036), pretransplant MELD score (16.43 ± 8.33 vs. 18.29 ± 9.05), rate of re‐transplantations, duration of surgery, demand in blood transfusions and rates of renal impairments. In the MELD era, higher incidences of IFI (pre‐MELD 11.9%, MELD 24.0%, P < 0.05) and Candida infections (9% vs. 18.9%, P < 0.05) were observed. There was no difference in the incidence of probable or possible aspergillosis. Mortality, length of stay in intensive care or hospital, and duration of mechanical ventilation did not differ between the pre‐MELD and MELD era. Regardless the date of transplantation, patients with fungi‐positive samples showed higher mortality rates than patients without. MELD score was analysed as independent predictors for posttransplant IFI. Higher MELD scores predispose to a more problematic postoperative course and are associated with an increase in fungal infections.