Brentuximab vedotin in combination with or without donor lymphocyte infusion for patients with Hodgkin lymphoma after allogeneic stem cell transplantation.

In our study, we evaluated the safety and efficacy of Brentuximab vedotin (BV) with or without the addition of donor lymphocyte infusion (DLI) after allogeneic stem cell transplantation (allo-SCT) in 16 patients with advanced Hodgkin lymphoma (HL). Thirteen patients with relapsed HL after allo-SCT received BV as treatment for active disease. Three patients without progression of HL after allo-SCT received BV as consolidation. Twelve patients had been previously exposed to BV for treatment of relapse after autologous-SCT. Ten out of 16 patients received BV in combination with DLI. Among the 13 patients treated for active disease, CR and PR was observed in 7 and 2 patients, respectively. With a median follow-up of 13 months, 13 out of 16 patients are alive, while 3 died because of disease progression. The median PFS was 6 months. DLI-associated GVHD occurred in seven patients. Five patients with GVHD required immunosuppression, and in all cases, GVHD resolved after a short course of low dose steroids, implying that an anti-GVHD modulating effect could be induced by the concurrent administration of BV. No serious adverse event was observed in any of the patients.

Fludarabine and treosulfan compared with other reduced-intensity conditioning regimens for allogeneic stem cell transplantation in patients with lymphoid malignancies.

Allogeneic stem-cell transplantation (SCT) is a potentially curative therapy for lymphoid malignancies. Myeloablative conditioning is associated with high non-relapse mortality (NRM). Reduced-intensity condition (RIC) reduces NRM but relapse rate is increased. Novel regimens with intensive anti-malignancy activity but limited toxicity are of benefit. We evaluated outcomes of 144 lymphoma patients given allogeneic SCT with RIC consisting of fludarabine and treosulfan (FT, n=50), intravenous-busulfan (FB2, n=38) or melphalan (FM, n=56). Sixty-nine patients (48%) had chemo-sensitive disease and 75 (52%) had chemo-refractory disease at SCT. The median follow-up is 39 months (4-149). Three-year survival was 67, 74 and 48% after FT, FB2 and FM, in chemo-sensitive disease (P=0.14) and 34, 11 and 17% in chemo-refractory disease, respectively (P=0.08). Three-year NRM was 24, 24 and 54% (P=0.002), whereas relapse mortality was 22, 34 and 18%, respectively (P=0.13). Multivariate analysis identified a high comorbidity-score, chemo-refractory disease and FM as associated with shortened survival. In conclusion, FB2 is associated with low NRM and good results in chemo-sensitive disease, but with higher relapse mortality rates. FM controls disease better, but with high NRM. FT probably balances these outcomes more optimally. It is as safe as FB2 and as cytoreductive as FM, resulting in improved outcome, mostly in advanced disease.

G-CSF-primed BM for allogeneic SCT: revisited.

G-SCF-mobilized PBSC (GPB) grafts have a higher cell dose and somewhat more committed progenitor cells than steady-state BM (SBM), resulting in faster engraftment and faster immunological reconstitution. On the other hand, transplant related mortality (TRM), disease-free survival (DFS) and overall survival (OS) are similar both for PB and for BM. In contrast to SBM, G-CSF-primed BM (GBM) grafts stimulate HSC proliferation, increasing cell dose and thus resulting in faster engraftment because of higher cell dose infused, or because of treatment with G-CSF. Furthermore, GBM may induce tolerance and functional modulations in donor hematopoiesis and immunity, further reducing GVHD incidence, which is already lower with SBM compared with GPB grafts. Overall, a growing body of clinical evidence suggests that GBM transplants may share the advantages of GPB transplantations, without the associated increased risk of GVHD, and might be an attractive graft source for allogeneic SCTs.

Allogeneic hematopoietic SCT for adults AML using i.v. BU in the conditioning regimen: outcomes and risk factors for the occurrence of hepatic sinusoidal obstructive syndrome.

I.v. BU is frequently used in the conditioning regimen prior to allogeneic hematopoietic SCT (allo-HSCT); however, overall outcomes, incidence of hepatic sinusoidal obstructive syndrome (SOS) and its risk factors are not well known. With this aim, we performed a study on 257 AML adult recipients. Seattle Criteria were used for diagnosis and classification of SOS. The median age was 44 years. Donors were HLA-identical siblings in 60%, HLA-matched unrelated in 29% and HLA mismatched in 11%. Conditioning regimen was myeloablative in 84% (i.v. BU with CY was the most frequently used regimen) and it was reduced intensity in 16% (i.v. BU associated with fludarabine). Acute and chronic GVHD was observed in 28% and 44%, respectively. Two-year incidence of non-relapse mortality was 16±2% and 2-year leukemia-free survival for patients in CR1, CR2 and non remission at HSCT were 55±4%, 58±7%, and 20±5%, respectively. At 6 months, incidence of SOS was 7.8±2%; and it was severe in eight patients (3%). Factors associated with the occurrence of SOS were: HLA-mismatched donor HSCT (P=0.002) and patients transplanted in non-remission (P=0.002). In conclusion, outcomes of HSCT using i.v. BU are encouraging in this setting, SOS incidence is low and it is influenced by the type of donor and disease status at the time of transplant.

Application of machine learning algorithms for clinical predictive modeling: a data-mining approach in SCT.

Data collected from hematopoietic SCT (HSCT) centers are becoming more abundant and complex owing to the formation of organized registries and incorporation of biological data. Typically, conventional statistical methods are used for the development of outcome prediction models and risk scores. However, these analyses carry inherent properties limiting their ability to cope with large data sets with multiple variables and samples. Machine learning (ML), a field stemming from artificial intelligence, is part of a wider approach for data analysis termed data mining (DM). It enables prediction in complex data scenarios, familiar to practitioners and researchers. Technological and commercial applications are all around us, gradually entering clinical research. In the following review, we would like to expose hematologists and stem cell transplanters to the concepts, clinical applications, strengths and limitations of such methods and discuss current research in HSCT. The aim of this review is to encourage utilization of the ML and DM techniques in the field of HSCT, including prediction of transplantation outcome and donor selection.

Secondary malignancies after allogeneic stem-cell transplantation in the era of reduced-intensity conditioning; the incidence is not reduced.

Secondary malignancies are well established complication in long-term survivors after allogeneic stem-cell transplantation (SCT) with myeloablative conditioning (MAC). Fludarabine-based reduced-intensity (RIC) and reduced-toxicity conditioning (RTC) regimens are increasingly used in the last decade; however, due to limited long-term follow-up, there is no data on secondary malignancies in this setting. The records of 931 consecutive patients given allogeneic SCT with MAC (n=257), RIC (n=449) or RTC (n=225), in a single institution over a 13-year period, were reviewed. Twenty-seven patients had secondary malignancy, diagnosed a median of 43 months (7 months-11.5 years) after SCT. The 10-year cumulative incidence was 5.6% (95% confidence interval (CI), 3.6-8.7), twice the expected rate in matched normal population. The incidence was 1.7, 7.4 and 5.7% after MAC, RIC and RTC, respectively (P=0.02). Multivariate analysis identified fludarabine-based conditioning (hazard ratio (HR) 3.5, P=0.05), moderate-severe chronic graft-versus-host disease (HR 2.8, P=0.01) and diagnosis of chronic myeloproliferative or non-malignant disease (HR 0.2, P=0.04) as risk-factors for secondary malignancy. The related 10-year mortality rate was 2.4% (95% CI, 1.0-5.4). In conclusion, the risk of secondary malignancies is not reduced and is even possibly increased in the era of fludarabine-based RIC/RTC. Patients and physicians should be aware of this association and life-long cancer screening is required for all transplant survivors.

Reduced-intensity conditioning allogeneic stem cell transplantation for relapsed/refractory mantle cell lymphoma: a multicenter experience.

BACKGROUND: Despite therapeutic approach that combines rituximab-containing chemotherapy, followed or not by autologous stem cell transplantation (auto-SCT), mantle cell lymphoma (MCL) patients experience relapses. Reduced-intensity conditioning allogeneic stem cell transplantation (RIC-allo-SCT) at time of relapse may represent an attractive strategy. PATIENTS AND METHODS: We report a multicenter retrospective analysis. Seventy MCL patients underwent RIC-allo-SCT in 12 centers. RESULTS: Median age at transplantation was 56 years and median time from diagnosis to transplantation was 44 months. The median number of previous therapies was 2 (range, 1-5) including autologous transplantation in 47 cases. At time of transplantation, 35 patients were in complete remission, 20 were in partial response and 15 in stable disease or progressive disease. The median follow-up for living patients was 24 months. The 2-year event-free survival (EFS) and overall survival (OS) rates were 50% and 53%, respectively. The 1- and 2-year transplant-related mortality rates were 22% and 32%, respectively. The statistical analysis demonstrated that disease status at transplantation was the only parameter influencing EFS and OS. CONCLUSIONS: These results suggest that RIC-allo-SCT may be an effective therapy in MCL patients with a chemo-sensitive disease at time of transplantation, irrespective of the number of lines of prior therapy. Studies are warranted to investigate the best type of RIC regimen.

Allo-SCT for AML and MDS with treosulfan compared with BU-based regimens: reduced toxicity vs reduced intensity.

Allo-SCT with reduced-intensity conditioning (RIC) results in lower non-relapse mortality (NRM), but higher relapse rate than myeloablative conditioning (MAC) in AML/myelodysplastic syndromes (MDS). Novel regimens with intensive anti-leukemic activity, but with limited toxicity will be of benefit. In all, 85 patients with AML/MDS, not eligible for MAC, were given fludarabine-treosulfan conditioning (FT). Outcomes were compared with those in patients given fludarabine-BU RIC (FB2, n=106) or reduced-toxicity (RTC) conditioning (FB4, fludarabine and myeloablative BU dose, n=85). The 5-year NRM was 29%, 20% and 18% after FT, FB2 and FB4, respectively (P=NS). Multivariate analysis (MVA) identified comorbidity score (HCT-CI) >2 and advanced disease as adverse factors with no independent impact of regimen. The 5-year relapse rate was 36%, 47% and 40%, respectively (P=0.17). MVA identified advanced disease as the major adverse factor, while FT had significantly lower relapse rate (hazard ratio 0.6, P=0.03). The 5-year survival (OS) was 37% with advanced disease. HCT-CI >2 and age ≥ 50 were found as adverse factors. The 5-year OS was 46%, 44% and 50% after FT, FB2 and FB4 in early-intermediate-stage disease (P=NS) and 33%, 9% and 28% in advanced disease, respectively (P=0.02). FT is an RTC regimen with intensive anti-leukemia effect in MAC non-eligible patients.

Treosulfan-based conditioning before hematopoietic SCT: more than a BU look-alike.

Allogeneic hematopoietic SCT is a curative treatment for a variety of hematological malignancies and genetic diseases. There is a continuous search for novel conditioning regimens that will reduce SCT-related toxicity while retaining maximal antimalignancy effect. Treosulfan (L-threitol-1,4-bis-methanesulfonate; dihydroxybusulfan) was initially used in the treatment of certain solid tumors. Preclinical studies showed that it has a myeloablative effect on committed and non-committed stem cells. It has potent immunosuppressive characteristics, more prominent than its related chemotherapy agent BU, which makes it an attractive candidate for the use in conditioning regimens before allo-SCT. It is also associated with a favorable toxicity profile with little extramedullary toxicity. The combination of fludarabine and treosulfan was explored in several studies in patients not eligible for standard myeloablative conditioning, and data are rapidly emerging. This regimen is associated with consistent engraftment. A limited non-relapse mortality (NRM) rate in the range of 9-28% was observed. This rate is promising considering the patients selected and results from low rates of organ toxicity as well as acute and chronic GVHD. The regimen was also associated with low relapse rates of 5-30% depending on disease status at SCT. Together with low NRM rate, this resulted in favorable survival in the range of 40-80%. Promising results were seen in myelodysplastic syndrome (survival 36-70%) and leukemia in remission (60-70%). Randomized prospective studies will be needed to better define the role of treosulfan-based regimens in SCT.

CT in the clinical and prognostic evaluation of acute graft-vs-host disease of the gastrointestinal tract.

OBJECTIVE: To determine the role of abdominal CT in assessment of severity and prognosis of patients with acute gastrointestinal (GI) graft-vs-host disease (GVHD). METHODS: During 2000-2004, 41 patients with a clinical diagnosis of acute GI-GVHD were evaluated. CTs were examined for intestinal and extra-intestinal abnormalities, and correlated with clinical staging and outcome. RESULTS: 20 patients had GVHD clinical Stage I-II and 21 had Stage III-IV. 39 (95%) had abnormal CT appearances. The most consistent finding was bowel wall thickening: small (n=14, 34%) or large (n=5, 12%) bowel, or both (n=20, 49%). Other manifestations included bowel dilatation (n=7, 17%), mucosal enhancement (n=6, 15%) and gastric wall thickening (n=9, 38%). Extra-intestinal findings included mesenteric stranding (n=25, 61%), ascites (n=17, 41%), biliary abnormalities (n=12, 29%) and urinary excretion of orally administered gastrografin (n=12, 44%). Diffuse small-bowel thickening and any involvement of the large bowel were associated with severe clinical presentation. Diffuse small-bowel disease correlated with poor prognosis. 8 of 21 patients responded to therapy, compared with 15 of 20 patients with other patterns (p=0.02), and the cumulative incidence of GVHD-related death was 62% and 24%, respectively (p=0.01). Overall survival was not significantly different between patients with diffuse small-bowel disease and patients with other patterns (p=0.31). Colonic disease correlated with severity of GVHD (p=0.04), but not with response to therapy or prognosis (p=0.45). CONCLUSION: GVHD often presented with abdominal CT abnormalities. Diffuse small-bowel disease was associated with poor therapeutic response. CT may play a role in supporting clinical diagnosis of GI GVHD and determining prognosis.

Clinical characteristics of Stenotrophomonas maltophilia infection in hematopoietic stem cell transplantation recipients: a single center experience.

BACKGROUND: Recipients of hematopoietic stem-cell transplantation (HSCT) are at high risk for infections caused by Stenotrophomonas maltophilia. METHODS: We conducted a retrospective analysis of all infections caused by S. maltophilia in HSCT recipients in a single center in Israel during a 4 year period. RESULTS: Of 570 patients undergoing HSCT, 19 patients with an invasive S. maltophilia infection were identified. Sixteen had allogeneic HSCT and 3 had autologous HSCT. Seventeen patients (90%) had an indwelling central venous catheter (CVC) at the time of infection. S. maltophilia infections were detected in three clinical settings: as a complication of prolonged neutropenia (n = 9), as a CVC-related non-neutropenic infection occurring after CVC manipulation (n = 8) and as a respiratory tract infection (n = 2). Eleven patients (58%) had a polymicrobial infection. Ten patients (52.6%) received carbapenems during the previous month. The treatment for all patients included broad spectrum antibiotics, which were switched according to susceptibilities upon identification of the isolates. All isolates were susceptible in vitro to TMP-SMX. CVCs were removed in 12 patients (70%). Six patients, all after allogeneic HSCT, died. The CVC was removed in only two of the five patients with CVCs who died. CONCLUSIONS: Stenotrophomonas maltophilia is an emerging nosocomial pathogen in HSCT recipients, both in the early neutropenic phase and in the non-neutropenic phase. It is commonly associated with the presence and manipulation of an indwelling CVC. Removal of the CVC in addition to appropriate antibiotic therapy (TMP-SMX) is crucial for infection control.

Pooled nasopharyngeal and oropharyngeal samples for the identification of respiratory viruses in adults.

A pooled sample of oropharyngeal swabs, nasopharyngeal swabs and nasopharyngeal washings, taken from each of 1,000 subjects, was compared to separate specimens from the same sampling. Multiplex real-time polymerase chain reaction (mqRT-PCR) was used to identify 12 respiratory viruses. Two hundred and forty-three (97%) of the 251 viruses identified in the separate samples were also identified in the mixed samples. The sensitivity rate was identical at 100% for all virus groups except coronaviruses. This sensitivity rate clearly justifies the use of pooled samples instead of separate samples for clinical and epidemiological purposes. The reduction in costs attained from the use of pooled samples may represent a critical advantage when considering its use in extensive clinical and epidemiological studies.

Two cycles of escalated BEACOPP followed by four cycles of ABVD utilizing early-interim PET/CT scan is an effective regimen for advanced high-risk Hodgkin's lymphoma.

BACKGROUND: Escalated combination therapy with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone (escBEACOPP) regimen is superior to cyclophosphamide, vincristine, procarbazine and prednisone alternating with doxorubicin, bleomycin, vinblastine and dacarbazine (COPP-ABVD) for advanced-stage Hodgkin's lymphoma (HL) patients. However, the original schedule of eight cycles of escBEACOPP was associated with significant toxicity. This study was conducted in an attempt to reduce the toxicity of the original schedule, while attempting to preserve improved initial tumor control. PATIENTS AND METHODS: Forty-five newly diagnosed patients with advanced-stage HL and International Prognostic Score > or = 3 received two initial cycles of escBEACOPP and then were evaluated by positron emission tomography (PET)/computed tomography scan. If a good imaging response was obtained, they were treated by four cycles of ABVD. RESULTS: Following the first two cycles of escBEACOPP, the overall response was 100% and at the end of all therapy, 40 (89%) patients were in complete response (disappearance of all clinical evidence of disease and PET negativity), three (7%) in partial response (PET-positive residual lesions and a size reduction of the majority of large masses by >50%), while two (4%) had progressive disease. After a median follow-up of 48 months, progression-free survival (PFS) and overall survival at 4 years were 78% and 95%, respectively. The 4-year PFS for early PET-negative patients (n = 31) and early PET-positive patients (n = 13) were 87% and 53%, respectively (P = 0.01). CONCLUSIONS: These data indicate that combined escBEACOPP-ABVD may improve the outcome in patients with high-risk advanced HL. The potential benefit of early-interim PET activity as a guide to continuing therapy in these patients merits further study in the future.

Impact of genetic abnormalities on survival after allogeneic hematopoietic stem cell transplantation in multiple myeloma.

We analyzed the prognostic impact of the most frequent genetic abnormalities detected by fluorescence in situ hybridization in 101 patients with multiple myeloma, who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after melphalan/fludarabine-based reduced conditioning. The incidences of abnormalities in the present analysis were as follows: del(13q14) (61%), t(11;14)(q13;q32) (14%), t(4;14)(p16.3;q32) (19%), MYC-gain gains (8q24) (21%), del(17p13) (16%) and t(14;16)(q32;q23) (5%). None of the patients had t(6;14)(p25;q32). The overall complete remission (CR) rate was 50% with no differences between the genetic abnormalities except for patients with del(17p13) who achieved less CR (7 vs 56%; P=0.001). Univariate analysis revealed a higher relapse rate in patients aged >50 years (P=0.002), patients with del(13q14) (P=0.006) and patients with del(17p13) (P=0.003). In multivariate analyses, only del(13q14) (HR: 2.34, P=0.03) and del(17p13) (HR: 2.24; P=0.04) significantly influenced the incidence of relapse, whereas for event-free survival, only age (HR 2.8; P=0.01) and del(17p13) (HR: 2.05; P=0.03) retained their negative prognostic value. These data show that del(17p13) is a negative prognostic factor for achieving CR as well as for event-free survival after HSCT. Translocation t(4;14) might be overcome by allogeneic HSCT, which will have implication for risk-adapted strategies.

Ibritumomab tiuxetan (Zevalin) combined with reduced-intensity conditioning and allogeneic stem-cell transplantation (SCT) in patients with chemorefractory non-Hodgkin's lymphoma.

Allogeneic SCT is an effective therapy for lymphoma. Reduced-intensity conditioning (RIC) reduces non-relapse mortality (NRM) associated with myeloablative conditioning but relapse rates are high when performed in active disease. This study was designed to explore the safety and outcome of ibritumomab tiuxetan (Zevalin) combined with RIC in patients with advanced lymphoma. The study included 12 patients, median age 54 years (37-62), with a median of four prior treatments (2-6) and active disease documented on PET-CT. Zevalin 0.4 mCi/kg was given on day -14 and fludarabine combined with BU (n=6) or melphalan (n=6) was started on day -6. GVHD prevention was tapered 3 months after SCT to augment the graft-versus-lymphoma effect. All patients engrafted, a median of 14 days after SCT. Eighty-three percent achieved CR/PR. With a median follow-up of 21 months (12-37), 2-year PFS is 33%. Only three patients relapsed; cumulative incidence 25%. NRM was 42%, predominantly due to acute GVHD. Zevalin-RIC is feasible with consistent engraftment, acceptable organ toxicity, but high rates of acute GVHD. The low incidence of relapse suggests augmented anti-lymphoma effect. Zevalin-RIC merits further study. Better results may be achieved in patients earlier in disease course and with longer duration of immune-suppression.

Comparison between two fludarabine-based reduced-intensity conditioning regimens before allogeneic hematopoietic stem-cell transplantation: fludarabine/melphalan is associated with higher incidence of acute graft-versus-host disease and non-relapse mortality and lower incidence of relapse than fludarabine/busulfan.

Reduced-intensity conditioning (RIC) regimens are increasingly used in allogeneic stem-cell transplantation (SCT). There are no data whether any of these regimens has advantage and in what setting. We retrospectively analyzed SCT outcomes in 151 patients given fludarabine-based RIC for various hematological malignancies; 72 conditioned with fludarabine and intravenous-busulfan (FB) and 79 with fludarabine and melphalan (FM). FM was more myelosuppressive. Grade III-IV organ toxicity occurred in 31 and 53% of FB and FM recipients (P=0.005) and acute graft-versus-host disease grade II-IV in 33 and 53%, respectively (P=0.01). Non-relapse mortality rate (NRM) was 16 and 40%, respectively (P=0.003). Active disease (HR 2.2, P=0.003) and prior autologous SCT (HR 1.7, P=0.04) predicted inferior overall survival (OS). Among patients transplanted in remission, OS was 72 and 36% after FB and FM, respectively (P=0.03) due to increased NRM with FM. Similarly, patients transplanted in active disease experienced higher NRM with FM, however lower relapse rates resulted in equivalent OS. In conclusion, there are marked differences in outcome between RIC regimens that are theoretically dose-equivalent. The FM regimen is more myelosuppressive and toxic but controls disease better. FB was associated with improved survival in patients transplanted in remission. These observations merit further study in prospective studies.