High total metabolic tumor volume at baseline predicts survival independent of response to therapy.

Early identification of ultra-risk diffuse large B-cell lymphoma (DLBCL) patients is needed to aid stratification to innovative treatment. Previous studies suggested high baseline total metabolic tumor volume (TMTV) negatively impacts survival of DLBCL patients. We analyzed the prognostic impact of TMTV and prognostic indices in DLBCL patients, aged 60 to 80 years, from the phase 3 REMARC study that randomized responding patients to R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) into maintenance lenalidomide or placebo. TMTV was computed on baseline positron emission tomography/computed tomography using the 41% maximum standardized uptake value method; the optimal TMTV cutoff for progression-free (PFS) and overall survival (OS) was determined and confirmed by a training validation method. There were 301 out of 650 evaluable patients, including 192 patients classified as germinal center B-cell-like (GCB)/non-GCB and MYC/BCL2 expressor. Median baseline TMTV was 238 cm3; optimal TMTV cutoff was 220 cm3. Patients with high vs low TMTV showed worse/higher Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2, stage III or IV disease, >1 extranodal site, elevated lactate dehydrogenase, International Prognostic Index (IPI) 3-5, and age-adjusted IPI 2-3. High vs low TMTV significantly impacted PFS and OS, independent of maintenance treatment. Although the GCB/non-GCB profile and MYC expression did not correlate with TMTV/survival, BCL2 >70% impacted PFS and could be stratified by TMTV. Multivariate analysis identified baseline TMTV and ECOG PS as independently associated with PFS and OS. Even in responding patients, after R-CHOP, high baseline TMTV was a strong prognosticator of inferior PFS and OS. Moreover, TMTV combined with ECOG PS may identify an ultra-risk DLBCL population. This trial was registered at www.clinicaltrials.gov as #NCT01122472.

A randomized phase II trial of azacitidine +/- epoetin-ß in lower-risk myelodysplastic syndromes resistant to erythropoietic stimulating agents.

The efficacy of azacitidine in patients with anemia and with lower-risk myelodysplastic syndromes, if relapsing after or resistant to erythropoietic stimulating agents, and the benefit of combining these agents to azacitidine in this setting are not well known. We prospectively compared the outcomes of patients, all of them having the characteristics of this subset of lower-risk myelodysplastic syndrome, if randomly treated with azacitidine alone or azacitidine combined with epoetin-ß. High-resolution cytogenetics and gene mutation analysis were performed at entry. The primary study endpoint was the achievement of red blood cell transfusion independence after six cycles. Ninety-eight patients were randomised (49 in each arm). Median age was 72 years. In an intention to treat analysis, transfusion independence was obtained after 6 cycles in 16.3% versus 14.3% of patients in the azacitidine and azacitidine plus epoetin-ß arms, respectively (P=1.00). Overall erythroid response rate (minor and major responses according to IWG 2000 criteria) was 34.7% vs. 24.5% in the azacitidine and azacitidine plus epoetin-ß arms, respectively (P=0.38). Mutations of the SF3B1 gene were the only ones associated with a significant erythroid response, 29/59 (49%) versus 6/27 (22%) in SF3B1 mutated and unmutated patients, respectively, P=0.02. Detection of at least one "epigenetic mutation" and of an abnormal single nucleotide polymorphism array profile were the only factors associated with significantly poorer overall survival by multivariate analysis. The transfusion independence rate observed with azacitidine in this lower-risk population, but resistant to erythropoietic stimulating agents, was lower than expected, with no observed benefit of added epoetin, (clinicaltrials.gov identifier: 01015352).

Naïve subset develops the most important alloreactive response among human CD4+ T lymphocytes in human leukocyte antigen-identical related setting.

In longitudinal clinical studies, receiving a high percentage of allogeneic donor-derived CD4(+) CCR7(+) T cells, which include naïve and central memory subsets have been correlated with increased incidence and severity of acute GVHD. Whether naïve and central memory CD4(+) T-cell subsets contribute more or equally to alloimmune responses are still unclear in human. The aim of this study was to investigate in vitro the alloreactive response of purified naïve, central memory, and effector memory CD4(+) T-cell subsets in HLA identical setting. By coculturing monocyte-derived dendritic cells and purified CD4(+) T-cell subsets, from healthy HLA-identical male and female sibling pairs, we found that naïve CD4(+) CCR7(+) CD45RA(+) T cells developed the highest proliferative response upon stimulation by minor histocompatibility antigens and were progressively driven to produce high levels of interferon-γ, tumor necrosis factor, and interleukin-6. Comparatively, the central memory CD4(+) CCR7(+) CD45RA(neg) subset proliferated to a lower extent and produced very low amounts of pro-inflammatory cytokines while the CCR7(neg) effector memory CD4(+) subset was unresponsive. This study demonstrates the superior capacity of naïve CD4(+) T cells to mount a primary alloreactive response as compared to central memory T cells. Their proliferative response associated with a pro-inflammatory differentiation makes them potentially acute GVHD inducers. These in vitro results in line with what we have observed in clinical studies and may also lend support to approaches of partial selective T-cell depletion for GVHD prevention.

Imatinib Optimized Therapy Improves Major Molecular Response Rates in Patients with Chronic Myeloid Leukemia.

The registered dose for imatinib is 400 mg/d, despite high inter-patient variability in imatinib plasmatic exposure. Therapeutic drug monitoring (TDM) is routinely used to maximize a drug's efficacy or tolerance. We decided to conduct a prospective randomized trial (OPTIM-imatinib trial) to assess the value of TDM in patients with chronic phase chronic myelogenous treated with imatinib as first-line therapy (NCT02896842). Eligible patients started imatinib at 400 mg daily, followed by imatinib [C]min assessment. Patients considered underdosed ([C]min < 1000 ng/mL) were randomized in a dose-increase strategy aiming to reach the threshold of 1000 ng/mL (TDM arm) versus standard imatinib management (control arm). Patients with [C]min levels ≥ 1000 ng/mL were treated following current European Leukemia Net recommendations (observational arm). The primary endpoint was the rate of major molecular response (MMR, BCR::ABL1IS ≤ 0.1%) at 12 months. Out of 133 evaluable patients on imatinib 400 mg daily, 86 patients had a [C]min < 1000 ng/mL and were randomized. The TDM strategy resulted in a significant increase in [C]min values with a mean imatinib daily dose of 603 mg daily. Patients included in the TDM arm had a 12-month MMR rate of 67% (95% CI, 51−81) compared to 39% (95% CI, 24−55) for the control arm (p = 0.017). This early advantage persisted over the 3-year study period, in which we considered imatinib cessation as a censoring event. Imatinib TDM was feasible and significantly improved the 12-month MMR rate. This early advantage may be beneficial for patients without easy access to second-line TKIs.

Daily practice management of myelodysplastic syndromes in France: data from 907 patients in a one-week cross-sectional study by the Groupe Francophone des Myelodysplasies.

BACKGROUND: There is little published information on the everyday clinical management of myelodysplastic syndromes in real world practice. DESIGN AND METHODS: We conducted a cross-sectional study of all patients with myelodysplastic syndromes attending 74 French centers in a 1-week period for inpatient admission, day-hospital care or outpatient visits. RESULTS: Nine hundred and seven patients were included; 67.3% had lower-risk myelodysplastic syndromes (International Prognostic Scoring System: low or intermediate-1). Karyotype had been analyzed in 82.5% of the cases and was more often of intermediate or poor risk in patients under 65 years old compared with those who were older. Red blood cell transfusions accounted for as many as 31.4% of the admissions. Endogenous erythropoietin level was less than 500 IU/L in 88% of the patients tested. Erythroid stimulating agents had been or were being used in 36.8% of the lower risk patients, iron chelation in 31% of lower risk patients requiring red blood cell transfusions and lenalidomide in 41% of lower risk patients with del 5q. High-dose chemotherapy, hypomethylating agents, low dose cytarabine and allogeneic stem cell transplantation had been or were being used in 14.8%, 31.1%, 8.8% and 5.1%, respectively, of higher-risk patients. CONCLUSIONS: Karyotype is now assessed in most patients with myelodysplastic syndromes, and patients under 65 years old may have more aggressive disease. Apart from erythroid-stimulating agents and, in higher-risk myelodysplastic syndromes, hypomethylating agents, specific treatments are used in a minority of patients with myelodysplastic syndromes and red blood cell transfusions still represent the major reason for hospital admission.

Autologous hematopoietic stem-cell transplant in small-sized and peripheral centers: a 10-year experiment.

BACKGROUND: Along with continuing changes in therapeutic modalities, indications of autologous hematopoietic stem-cell transplantation (ASCT) have been emerging and changing considerably, especially in the era of targeted therapy and small molecule inhibitors. Patients treated with novel agents tend to have a longer survival period, thus eventually reaching higher ages at ASCT. Herein, and to address the question of ASCT outcomes in small, community-based, peripheral French centers, we report the 10-year follow-up results of 136 patients who received ASCT in our eight-bed ASCT unit, situated in an urban area. METHODS: We retrospectively analyzed a cohort of 136 patients treated between 2008 and 2017 at the Duchenne Hospital Center. Of these 136 patients, 75 underwent ASCT for myeloma, while 61 underwent ASCT for lymphoma, amongst which 57 patients were treated for B-cell lymphoma. The median age was 65 years (range, 27-72) for myeloma patients, and 62 years (range, 27-71) for patients with lymphoma. RESULTS: The cohort median follow up was estimated at 33 months; 10-year overall survival (OS) and progression-free survival (PFS) were 71% and 64% for B-cell non-Hodgkin lymphoma, and 75% and 45% for myeloma, respectively. No statistically significant differences were found for OS or 1-year PFS between patients who received ASCT from 2008 to 2012, and those who received it from 2013 to 2017. CONCLUSIONS: In the absence of randomized trials studying the role of center size, experience, and standardization procedure for ASCT outcome, these results may suggest that ASCT in peripheral accredited small-sized centers could be a viable option to facilitate follow up and enable access to this treatment, especially for elderly patients, in comparison with referring the patient to central large hospitals to undergo ASCT.

Ibrutinib Treatment through Nasogastric Tube in a Comatose Patient with Central Nervous System Localization of Mantle Cell Lymphoma.

Nowadays, mantle cell lymphoma is considered to have one of the worst prognostic profiles among lymphoid malignancies. Mantle cell lymphoma rarely affects the central nervous system (CNS) as it represents about 0.9% of diagnosis and 4% among recurrent cases. Here, we present the case of a 69-year-old male patient who was diagnosed with mantle cell lymphoma in 2006. The patient relapsed three times, without affecting the CNS, then was treated accordingly, and achieved complete remission three times. Four years after his last complete remission, upon receiving his last dose of treatment, the medical team noted a rapid worsening of the patient's neurological status followed by a deep coma state causing MCL neurological recurrence by exclusion diagnosis. The patient then received ibrutinib via a nasogastric tube at a dose of 560 mg daily. Two days after receiving his last dose of ibrutinib, the patient regained full consciousness, and 10 days later, he was discharged from the hospital. The patient achieved complete remission and showed no signs of neurological damages for 24 months following his ibrutinib treatment. We believe that the administration of ibrutinib through the nasogastric tube was a determinant factor in this patient's remission and survival.

Durable Resolution of Severe Psoriasis in a Patient Treated with Pentostatin for Hairy Cell Leukemia: A Case Report.

INTRODUCTION: Pentostatin (2'-deoxycoformycin) and cladribine (2-chlorodeoxyadenosine) are adenosine analogues widely used to treat lymphoid malignancies, mainly hairy cell leukemia (HCL). Oral or parenteral adenosine analogues have been also used as immunomodulatory agents in multiple sclerosis and in acute graft-versus-host disease. CASE REPORT: Here, we report the case of a 43-year-old patient with a history of extensive psoriasis who later developed HCL. RESULTS: The patient had achieved complete remission of both psoriasis and HCL after receiving intravenous infusions of pentostatin. It is worth noting that cladribine has already been reported to treat plaque psoriasis lesions in two patients with HCL and in a third patient with gastric marginal zone B cell lymphoma [1]. CONCLUSION: We believe that adenosine analogues constitute a promising therapeutic option for moderate to severe psoriasis, especially for severe and refractory psoriasis, as well as for patients with adjacent lymphoid malignancies.

Combination of ofatumumab and reduced-dose CHOP for diffuse large B-cell lymphomas in patients aged 80 years or older: an open-label, multicentre, single-arm, phase 2 trial from the LYSA group.

BACKGROUND: In 2011 we reported a rituximab plus miniCHOP (reduced-dose cyclophosphamide, doxorubicin, vincristine, and prednisone) combination for patients older than 80 years with diffuse large B-cell lymphoma (DLBCL). The 2-year overall survival was 59% (95% CI 49-67) with an excess of early toxicity. To improve those results we tested the same chemotherapy protocol in combination with ofatumumab and a pre-phase treatment. METHODS: For this open-label, multicentre, single-group, phase 2 trial, we recruited patients older than 80 years with untreated histologically-proven CD20-positive DLBCL, Ann Arbor stage I to IV, from 41 academic and hospital centres in France and Belgium. Patients received a pre-phase with oral vincristine (1 mg total dose 1 week before cycle 1 [day -7]) and oral prednisone (60 mg total dose starting 1 week before cycle 1, for 4 days [day -7 to day -4]) before the first cycle of the ofatumumab plus miniCHOP regimen. The regimen consisted of 1000 mg total dose of intravenous ofatumumab, 25 mg/m2 of intravenous doxorubicin, 400 mg/m2 of intravenous cyclophosphamide, and 1 mg of intravenous vincristine, on day 1 of each cycle; and 40 mg/m2 of oral prednisone on days 1-5. Ofatumumab was administered with 1000 mg of paracetamol and 50 mg of diphenhydramine. The primary endpoint was overall survival in the intention-to-treat population. The statistical analysis has been done on an intention-to-treat principle. This study was registered with ClinicalTrials.gov, number NCT01195714. FINDINGS: Between June 2, 2010, and Nov 4, 2011, we enrolled 120 patients. Age-adjusted International Prognostic Index was 2-3 in 68 (57%) of them. The median follow-up time was 26·8 months (IQR 24·5-30·1). The 2-year overall survival was 64·7% (95% CI 55·3-72·7) and median overall survival was not reached (95% CI 30·2-not reached). 45 patients died during the treatment, of whom 28 (62%) died due to lymphoma. The most common side-effect was haematological toxicity. Among the 120 patients, grade 3-4 neutropenia was reported in 24 (21%) patients and thrombocytopenia in two (2%), during the treatment period. Grade 3-4 anaemia was reported in six (5%) patients; seven (6%) patients had one episode of febrile neutropenia. 17 (15%) of 115 patients in the modified intention-to-treat population had red blood cell transfusions and three (3%) had platelet transfusions. INTERPRETATION: Our result suggest that, in patients older than 80 years with DLBCL, ofatumumab and pre-phase treatment seem to improve overall survival compared with the previously reported data. The combination of pre-phase treatment, a monoclonal antibody against CD20, and miniCHOP can be considered a new treatment platform for use in randomised clinical trial design for DLBCL treatment in patients older than 80 years. FUNDING: The Lymphoma Study Association, GlaxoSmithKline.

Lenalidomide Maintenance Compared With Placebo in Responding Elderly Patients With Diffuse Large B-Cell Lymphoma Treated With First-Line Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone.

Purpose The standard treatment of patients with diffuse large B-cell lymphoma (DLBCL) is rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Lenalidomide, an immunomodulatory agent, has shown activity in DLBCL. This randomized phase III trial compared lenalidomide as maintenance therapy with placebo in elderly patients with DLBCL who achieved a complete response (CR) or partial response (PR) to R-CHOP induction. Methods Patients with previously untreated DLBCL or other aggressive B-cell lymphoma were 60 to 80 years old, had CR or PR after six or eight cycles of R-CHOP, and were randomly assigned to lenalidomide maintenance 25 mg/d or placebo for 21 days of every 28-day cycle for 24 months. The primary end point was progression-free survival (PFS). Results A total of 650 patients were randomly assigned. At the time of the primary analysis (December 2015), with a median follow-up of 39 months from random assignment, median PFS was not reached for lenalidomide maintenance versus 58.9 months for placebo (hazard ratio, 0.708; 95% CI, 0.537 to 0.933; P = .01). The result was consistent among analyzed subgroups (eg, male v female, age-adjusted International Prognostic Index 0 or 1 v 2 or 3, age younger than 70 v ≥ 70 years), response (PR v CR) after R-CHOP, and positron emission tomography status at assignment (negative v positive). With longer median follow-up of 52 months (October 2016), overall survival was similar between arms (hazard ratio, 1.218; 95% CI, 0.861 to 1.721; P = .26). Most common grade 3 or 4 adverse events associated with lenalidomide versus placebo maintenance were neutropenia (56% v 22%) and cutaneous reactions (5% v 1%), respectively. Conclusion Lenalidomide maintenance for 24 months after obtaining a CR or PR to R-CHOP significantly prolonged PFS in elderly patients with DLBCL.

Does bendamustine impact the mobilization of peripheral blood stem cells? A multicenter retrospective study of 23 cases.

Bendamustine is used in the treatment of different relapsing or refractory subtypes of lymphoma. Its impact on the yield of peripheral blood stem cells is not well known. Twenty three patients who received bendamustine followed immediately or after another chemotherapy by stem cell mobilization (SCM) were included. The patients were divided into two groups: group 1 (n=17), in whom SCM was performed immediately after bendamustine chemotherapy, and group 2 (n=6), in whom SCM was performed after another cycle of chemotherapy. The success rate of mobilization after Bendamustine+/-plerixafor was 36% (eight cytapheresis succeeded for a total number of 22 cytapheresis); and 75% after other approaches (chemotherapy based or steady state) used for patients who received bendamustine previously. Although bendamustine used alone was not an effective drug to mobilize stem cells, this agent does not seem to have detrimental effects on subsequent SCM.

Bendamustine for the treatment of relapsed or refractory peripheral T cell lymphomas: A French retrospective multicenter study.

Peripheral T-cell lymphoma (PTCL) is a group of diseases with poor outcome and few therapeutic options. We aimed to assess the efficacy of bendamustine in real life cohort of patients.Between November 2009 and March 2015, 138 PTCL patients were treated with bendamustine in 27 centers. Population median age was 64 (28-89) years with male/female ratio of 1.4. There were mainly angio-immunoblastic (AITL = 71), PTCL-not otherwise specified (PTCL-NOS = 40) and anaplastic large cell lymphoma (ALCL = 8). The majority of patients (96%) had disseminated disease and extranodal localizations (77%). Median number of chemotherapy lines prior to bendamustine was 2 (1-8). Median duration of response (DoR) after the last chemotherapy prior to bendamustine was 4.3 months (1-70) and 50% of patients had refractory disease.Median number of administered bendamustine cycles was 2 (1-8) and 72 patients (52%) received less than 3 mostly because of disease progression. Median dose was 90 (50-150) mg/m². Overall response rate (ORR) was 32.6% with complete response (CR) rate of 24.6% and median DoR was 3.3 months (1-39). AITL patients were more sensitive than PTCL-NOS patients (ORR: 45.1 versus 20%, p = 0.01). Median PFS and OS were 3.1 (0.2-46.3) and 4.4 (0.2-55.4) months. On multivariate analysis, refractory disease (p = 0.001) and extranodal localization (p = 0.028) adversely influenced ORR. Grade 3-4 thrombocytopenia, neutropenia and infections were reported in 22, 17 and 23% of cases respectively.Bendamustine as single agent could be considered as a therapeutic option for relapsed or refractory PTCL, particularly in chemosensitive or AITL patients. Combinations of bendamustine with other drugs warrant further evaluation.

Results from a prospective, open-label, phase II trial of bendamustine in refractory or relapsed T-cell lymphomas: the BENTLY trial.

PURPOSE: To determine the efficacy and safety of bendamustine as a single agent in refractory or relapsed T-cell lymphomas. PATIENTS AND METHODS: Patients with histologically confirmed peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma who progressed after one or more lines of prior chemotherapy received bendamustine at 120 mg/m(2) per day on days 1 through 2 every 3 weeks for six cycles. The primary end point was overall response rate (ORR). Secondary end points were duration of response (DOR), progression-free survival (PFS), and overall survival (OS). RESULTS: Of the 60 patients included, 27 (45%) were refractory to their last prior chemotherapy, and the median duration of the best previous response was 6.6 months. Histology was predominantly angioimmunoblastic lymphadenopathy and PTCL not otherwise specified. The disease was disseminated in the majority of patients (87%). The median number of previous lines of chemotherapy was one (range, one to three). Twenty patients (33%) received fewer than three cycles of bendamustine, mostly because of disease progression. In the intent-to-treat population, the ORR was 50%, including complete response in 17 patients (28%) and partial response in 13 patients (22%). Bendamustine showed consistent efficacy independent of major disease characteristics. The median values for DoR, PFS, and OS were 3.5, 3.6, and 6.2 months, respectively. The most frequent grade 3 to 4 adverse events were neutropenia (30%), thrombocytopenia (24%), and infections (20%). CONCLUSION: Bendamustine showed an encouraging high response rate across the two major PTCL subtypes, independent of age and prior treatment, with acceptable toxicity in refractory or relapsed T-cell lymphoma.

[Hematopoietic growth factors and autologous or allogeneic stem cell transplantation]. / Utilisation des facteurs de croissance hématopoïétiques et transplantation de cellules souches d'origine autologue ou allogénique.

Hematopoietic growth factors are usually administered in autologous and allogeneic stem cell transplantation. RhuG-CSF and rhuEPO are the most frequently used, either for mobilization of peripheral stem cells or after transplantation for the improvement of hematologic recovery. G-CSF (filgrastim or lenograstim) can be administered alone or in combination with stem cell factor to enhance stem cells mobilization. IL-3 and sargramostim are not used anymore. The protocol of administration of rhuG-CSF is well established. Furthermore, stem cell transplantation with peripheral cells is less expensive than with bone marrow. RhuEPO (erythropoietin) is not effective in mobilization. After transplantation, filgrastim or lenograstim can shorten the neutropenic period and decrease infectious complications. The potential effect of these growth factors on the incidence and the severity of GvHD is still unknown and under debate. The use of rhuEPO after transplantation might be of interest to reduce the need of red blood cell transfusion. Some studies suggest that the administration of rhuEPO should start before delivering the conditioning regimen. The new long acting growth factors such as pegfilgrastim are still under evaluation and their use in mobilization seems promising.

Gene Expression in Human Acute Cutaneous and Hepatic Graft-Versus-Host Disease after Allogeneic Bone Marrow Transplantation.

Hematopoietic stem cell (HSC) allograft can be performed with cells of peripheral or medullar origin. Currently, it is the best therapy for certain malignant diseases. The curative power of allografts is based on conditioning and on the graft versus leukemia (GVL) effect. This effect is always associated with a toxic reaction called graft-versus-host disease (GVHD). Numerous studies have been carried out on mouse models, but the pathophysiology of GVHD remains unknown. To evaluate the variation in gene expression during GVHD, a prospective study was performed on two patients with GVHD, using the donors as controls. Blood lymphocytes were isolated by Ficoll gradient. The gene expression levels in total RNA were determined using the Taqman method. The gene expressions of cytokines (TNFα, INFγ, IL4, IL10), major histocompatibility complex class II (MHC II) and class III (BAT2), an adhesion molecule (VCAM) and granzyme M were studied. INFγ, TNFα, BAT2 and IL4 were up-regulated whereas IL10 and VCAM1 were down-regulated.

Graft-versus-host disease following allogeneic transplantation from HLA-identical sibling with antithymocyte globulin-based reduced-intensity preparative regimen.

Reduced-intensity conditioning (RIC) regimens are increasingly used for allogeneic stem cell transplantation (allo-SCT). RIC has been shown to allow engraftment with minimal early transplantation-related mortality (TRM). However, in the context of RIC, predictive factors for acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively) and their effect on outcome remain unknown. In this report, we analyzed the outcome of 101 high-risk patients (70 hematologic and 31 nonhematologic malignancies) who received an HLA-identical sibling allo-SCT after RIC, including fludarabine, busulfan, and antithymocyte globulin (ATG). The cumulative incidence of grade II-IV aGVHD was 36% (95% confidence interval [CI], 27%-45%), whereas the cumulative incidence of cGVHD at 2 years was 43% (95% CI, 33%-53%). In multivariate analysis, the incidence of aGVHD was significantly associated with the ATG dose infused during conditioning (P =.0005), whereas peripheral blood as stem cell source was the only predictive factor for the development of cGVHD (P =.0007). The 1-year cumulative incidences of disease progression or relapse in patients with (n = 69) and without (n = 31) GVHD (whatever its form or grade) were 30% (95% CI, 19%-41%) and 55% (95% CI, 37%-72%), respectively (P =.02), suggesting that a potent graft-versus-tumor (GVT) effect can be achieved in high-risk patients following RIC. Moreover, the GVT effect was closely associated with GVHD without an increased risk of TRM (cumulative incidence of TRM, 18% [95% CI, 10%-25%]). Collectively, these results provide a framework for the refinement of RIC approaches designed to enhance the GVT effect with an acceptable risk of GVHD.

Reduced-intensity preparative regimen and allogeneic stem cell transplantation for advanced solid tumors.

In this prospective multicenter program, we investigated allogeneic stem cell transplantation (ASCT) from HLA-identical siblings following reduced-intensity conditioning (RIC) regimen for patients with refractory metastatic solid tumors (STs). Fifty-seven patients, of whom 39 had a progressive disease (PD) at time of ASCT, received an RIC ASCT combining fludarabine, antithymocyte globulin (ATG), and busulfan. Patients were analyzed in terms of engraftment, transplant-related mortality (TRM), disease response, and outcome. In this setting, RIC was associated with rapid engraftment and low overall TRM (9% [95% confidence interval (CI), 1%-16%]). The cumulative incidence of objective responses (ORs) reached 14% (95% CI, 6%-30%) with this being significantly higher in patients without PD (44% [95% CI, 21%-67%] versus 0; P <.0001) at time of ASCT. Achievement of OR translated into a significantly better overall survival (OS). In multivariate analysis, OS was significantly influenced by disease status at time of ASCT (odds ratio, 4.88; P <.001) and chronic graft-versus-host disease (GVHD) occurrence (odds ratio, 2.86; P <.01). Overall, these results showed that OR can occur after RIC ASCT for resistant ST with a relatively low TRM and potential benefit especially in patients with slowly progressive disease. Further studies are warranted in patients with less advanced ST.