High-dose chemotherapy and autologous stem cell transplant as first salvage treatment for relapsed or refractory Hodgkin Lymphoma in the era of PET-adapted strategies.

Data on the efficacy of high-dose chemotherapy and autologous stem cell transplantation (ASCT) for classical Hodgkin lymphoma (cHL) patients who failed a PET-driven first-line therapy are limited.We retrospectively evaluated 220 adult cHL patients who underwent ASCT from 2009 to 2021 at 11 centers in Italy. Overall, 49.5% had refractory disease, 23.2% relapsed < 12 and 27.3% ≥12 months from the end of first-line chemotherapy. The 3-year progression-free survival (PFS) and overall survival (OS) were 73.8% and 89.4%. In univariable analysis for PFS events PET-2+ (HR 2.69, p = .001), anemia (HR 2.22, p = .019), refractory disease (HR 1.76, p = .045), less than CR before ASCT (HR 3.24, p < .001) and >2 lines of salvage therapy (HR 2.52; p = .004) were associated with a higher risk of failure after ASCT. In multivariable analysis, >2 lines of salvage therapy (HR 3.28, p = .004) and RT before ASCT (HR 3.00, p = 0.041) retained significance.ASCT is an effective salvage approach for cHL patients treated in the era of PET-adapted therapies.

Predictive value on advance hodgkin lymphoma treatment outcome of end-of treatment FDG PET/CT in the HD0607 clinical trial.

The Lugano classification for response assessment in lymphoma recommends the use of the 5-point-scale Deauville Score (DS) to assess response evaluation of end-of-treatment FDG-PET/CT (eotPET) in Hodgkin Lymphoma (HL); nevertheless, there is a paucity of data on its accuracy and reproducibility. We focus here on the cohort of advanced stage IIb-IV HL patients enrolled in the HD0607 clinical trial (NCT identifier 00795613) that having had a negative interim PET performed 6 cycles of ABVD (Doxorubicin, Vinblastine, Vincristine and Dacarbazine) and then performed an eotPET. Negative patients were randomized to radiotherapy and no further treatment while positive patients were treated based on local policies. eotPET was re-evaluated independently by two readers evaluated and progression free survival was analysed (PFS). eotPET of 254 patients were analysed. The median follow-up was 43 months. The best receiver operator characteristics cut-off values to distinguish positive and negative patients was 4. The area-under-the-curve was 0.81 (95%CI, 0.70-0.91). Three-years PFS was 0.95 (95% CI 0.90-0.97) in eotPET negative and 0.22 (95% CI 0.11-0.43) in eotPET positive. DS demonstrated a good reproducibility of positivity/negativity between the readers consensus and local site evaluation where the agreement occurred on 95.0% of patients. The present study demonstrates that eotPET is an accurate tool to predict treatment outcome in HL and confirms the appropriateness of the Lugano classification for eotPET evaluation.

Myeloablative conditioning with thiotepa-busulfan-fludarabine does not improve the outcome of patients transplanted with active leukemia: final results of the GITMO prospective trial GANDALF-01.

The outcome of refractory/relapsed (R/R) acute leukemias is still dismal and their treatment represents an unmet clinical need. However, allogeneic transplantation (allo-HSCT) remains the only potentially curative approach in this setting. A prospective study (GANDALF-01, NCT01814488; EUDRACT:2012-004008-37) on transplantation with alternative donors had been run by GITMO using a homogeneous myeloablative conditioning regimen with busulfan, thiotepa and fludarabine while GVHD prophylaxis was stratified by donor type. The study enrolled 101 patients; 90 found an alternative donor and 87 ultimately underwent allo-HSCT. Two-year overall survival of the entire and of the transplant population (primary endpoint) were 19% and 22%, without significant differences according to disease, donor type and disease history (relapsed vs refractory patients). Two-year progression-free survival was 19% and 17% respectively. The cumulative incidences of relapse and non-relapse mortality were 49% and 33% at two years. Acute grade II-IV and chronic GVHD occurred in 23 and 10 patients. Dose intensification with a myeloablative two-alkylating regimen as sole strategy for transplanting R/R acute leukemia does seem neither to improve the outcome nor to control disease relapse. A pre-planned relapse prevention should be included in the transplant strategy in this patient population.

Dose-dense ABVD as first-line therapy in early-stage unfavorable Hodgkin lymphoma: results of a prospective, multicenter double-step phase II study by Fondazione Italiana Linfomi.

We investigated the feasibility and activity of an intensified dose-dense ABVD (dd-ABVD) regimen in patients with early-stage unfavorable Hodgkin lymphoma (HL). This prospective, multicenter, phase II study enrolled 96 patients with newly diagnosed, unfavorable stage I or II classical HL. The patients received four cycles of dd-ABVD followed by radiotherapy. Interim PET (PET-2) was mandatory after two courses. Primary endpoints were the evaluation of dd-ABVD feasibility and activity (incidence of PET-2 negativity). The feasibility endpoint was achieved with 48/52 (92.3%) patients receiving > 85% of the programmed dose. The mean dose intensity in the overall patient population (n = 96) was 93.7%, and the median duration of dd-ABVD was 85 days (range, 14-115) versus an expected duration of 84 days. PET-2 was available for 92/96 (95.8%) patients, of whom 79 were PET-2 negative (85.9%). In total, 90 (93.8%) patients showed complete response at the end of treatment. With a follow-up of 80.9 months (3.3-103.2), the median progression-free survival (PFS) and overall survival (OS) were not reached. At 84 months, PFS and OS rates were 88.4% and 95.7%, respectively. No evidence for a difference in PFS or OS was observed for PET-2-negative and PET-2-positive patients. Infections were documented in 8.3% and febrile neutropenia in 6.2% of cases. Four patients died: one had alveolitis at cycle 3, one death was unrelated to treatment, and two died from a secondary cancer. dd-ABVD is feasible and demonstrates activity in early-stage unfavorable HL. The predictive role of PET-2 positivity in early-stage unfavorable HL remains controversial. The study was registered in the EudraCT (reference number, 2011-003,191-36) and the ClinicalTrials.gov (reference number, NCT02247869) databases.

Impact of anti-thymocyte globulin dose for graft-versus-host disease prophylaxis in allogeneic hematopoietic cell transplantation from matched unrelated donors: a multicenter experience.

Despite the widespread use of rabbit anti-thymocyte globulin (ATG) to prevent acute and chronic graft-versus-host disease (aGVHD, cGVHD) after allogeneic hematopoietic cell transplantation (allo-HCT), convincing evidence about an optimal dose is lacking. We retrospectively evaluated the clinical impact of two different ATG doses (5 vs 6-7.5 mg/kg) in 395 adult patients undergoing HSCT from matched unrelated donors (MUD) at 3 Italian centers. Cumulative incidence of aGVHD and moderate-severe cGVHD did not differ in the 2 groups. We observed a trend toward prolonged overall survival (OS) and disease-free survival (DFS) with lower ATG dose (5-year OS and DFS 56.6% vs. 46.3%, p=0.052, and 46.8% vs. 38.6%, p=0.051, respectively) and no differences in relapse incidence and non-relapse mortality. However, a significantly increased infection-related mortality (IRM) was observed in patients who received a higher ATG dose (16.7% vs. 8.8% in the lower ATG group, p=0.019). Besides, graft and relapse-free survival (GRFS) was superior in the lower ATG group (5-year GRFS 43.1% vs. 32.4%, p=0.014). The negative impact of higher ATG dose on IRM and GRFS was confirmed by multivariate analysis. Our results suggest that ATG doses higher than 5 mg/kg are not required for MUD allo-HCT and seem associated with worse outcomes.

Diagnosis of maternal Hodgkin lymphoma following abnormal findings at noninvasive prenatal screening test (NIPT): Report of two cases.

Abnormal NIPT results, contrasting with normal fetus development, could disclose maternal malignancy, and this possibility should always be explained during pretest counseling. In this case, a complete diagnostic assessment is recommended and should be managed by a multidisciplinary team to define the best timing for diagnostic procedures, delivery, and treatment.

Donor Lymphocyte Infusions After Allogeneic Stem Cell Transplantation in Acute Leukemia: A Survey From the Gruppo Italiano Trapianto Midollo Osseo (GITMO).

We conducted a retrospective multicenter study including pediatric and adult patients with acute leukemia (AL) who received donor lymphocyte infusions (DLIs) after allogeneic hematopoietic stem cell transplantation (HCT) between January 1, 2010 and December 31, 2015, in order to determine the efficacy and toxicity of the immune treatment. Two hundred fifty-two patients, median age 45.1 years (1.6-73.4), were enrolled from 34 Italian transplant centers. The underlying disease was acute myeloid leukemia in 180 cases (71%). Donors were HLA identical or 1 locus mismatched sibling (40%), unrelated (40%), or haploidentical (20%). The first DLI was administered at a median time of 258 days (55-3,784) after HCT. The main indication for DLI was leukemia relapse (73%), followed by mixed chimerism (17%), and pre-emptive/prophylactic use (10%). Ninety-six patients (38%) received one single infusion, whereas 65 (26%), 42 (17%), and 49 patients (19%) received 2, 3, or ≥4 infusions, respectively, with a median of 31 days between two subsequent DLIs. Forty percent of evaluable patients received no treatment before the first DLI, whereas radiotherapy, conventional chemotherapy or targeted treatments were administered in 3, 39, and 18%, respectively. In informative patients, a few severe adverse events were reported: grade III-IV graft versus host disease (GVHD) (3%), grade III-IV hematological toxicity (11%), and DLI-related mortality (9%). Forty-six patients (18%) received a second HCT after a median of 232 days (32-1,390) from the first DLI. With a median follow-up of 461 days (2-3,255) after the first DLI, 1-, 3-, and 5- year overall survival (OS) of the whole group from start of DLI treatment was 55, 39, and 33%, respectively. In multivariate analysis, older recipient age, and transplants from haploidentical donors significantly reduced OS, whereas DLI for mixed chimerism or as pre-emptive/prophylactic treatment compared to DLI for AL relapse and a schedule including more than one DLI significantly prolonged OS. This GITMO survey confirms that DLI administration in absence of overt hematological relapse and multiple infusions are associated with a favorable outcome in AL patients. DLI from haploidentical donors had a poor outcome and may represent an area of further investigation.

Consolidation Radiotherapy Could Be Safely Omitted in Advanced Hodgkin Lymphoma With Large Nodal Mass in Complete Metabolic Response After ABVD: Final Analysis of the Randomized GITIL/FIL HD0607 Trial.

PURPOSE: To investigate the role of consolidation radiotherapy (cRT) in advanced-stage Hodgkin lymphoma (HL) presenting at baseline with a large nodal mass (LNM) in complete metabolic response after doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy. PATIENTS AND METHODS: Advanced-stage (IIB-IVB) HL patients, enrolled in the HD 0607 trial (Clinicaltrial.gov identifier NCT00795613), with both a negative PET after two (PET-2) and six (PET-6) ABVD cycles, who presented at baseline with an LNM, defined as a nodal mass with the largest diameter ≥ 5 cm, were prospectively randomly assigned to receive cRT over the LNM or no further treatment (NFT). RESULTS: Among 296 randomly assigned patients, the largest diameter of LNM at baseline was 5-7 cm in 101 (34%; subgroup A) and 8-10 cm in 96 (32%; subgroup B), whereas classic bulky (diameter > 10 cm) was detected in 99 (33%; subgroup C). Two hundred eighty patients (88%) showed a postchemotherapy RM. The median dose of cRT was 30.6 Gy (range, 24-36 Gy). After a median follow-up of 5.9 years (range, 0.5-10 years), the 6-year progression-free survival rate of patients who underwent cRT or NFT was, respectively, 91% (95% CI, 84% to 99%) and 95% (95% CI, 89% to 100%; P = .62) in subgroup A; 98% (95% CI, 93% to 100%) and 90% (95% CI, 80% to 100%; P = .24) in subgroup B; 89% (95% CI, 81% to 98%) and 86% (95% CI, 77% to 96%; P = .53) in subgroup C (classic bulky). CONCLUSION: cRT could be safely omitted in patients with HL presenting with an LNM and a negative PET-2 and PET-6 scan, irrespective from the LNM size detected at baseline.

Early serum TARC reduction predicts prognosis in advanced-stage Hodgkin lymphoma patients treated with a PET-adapted strategy.

Among patients with advanced-stage classical Hodgkin lymphoma (cHL) receiving ABVD chemotherapy, PET performed after the first two treatment cycles (PET-2) has prognostic value. However, 15% of patients with a negative PET-2 will experience treatment failure. Here we prospectively evaluated serum thymus and activation-regulated chemokine (TARC) levels, to improve risk assessment in patients treated according to HD0607 PET-driven trial (#NCT00795613). In 266 patients with available serum samples, who have agreed to participate in a sub-study for assessment of the role of TARC monitoring, serum TARC levels were measured at baseline and at time of PET-2 by commercially available ELISA test kits. The primary end-point was to evaluate the association between TARC after 2 ABVD cycles and PFS. Median TARC-2 values were significantly higher in PET-2-positive patients compared to PET-2-negative patients (P = .001), and in patients with treatment failure compared to those in continuous CR (P = .01). The 4-year PFS significantly differed between patients with TARC-2 >800 pg/mL vs ≤800 pg/mL (64% vs 86%, P = .0001). Moreover, among PET-2-negative patients, elevated TARC-2 identified those with a worse prognosis (74% vs 89%; P = .01). In multivariable analysis, TARC-2 >800 pg/mL was a significant independent predictor of PFS in the whole study population (HR 2.39, P = .004) and among the PET-2-negative patients (HR 2.49, P = .02). In conclusion, our results indicate that TARC-2 serum levels above 800 pg/mL suggest the need for a stringent follow-up in PET-2-negative patients, and the evaluation of new drugs in PET-2-positive, who will likely fail to respond to intensification with escalated BEACOPP.

Relapsing/refractory HL after autotransplantation: which treatment?

For advanced-stage Hodgkin lymphoma (HL), front-line chemotherapy, alone or in combination with radiotherapy, leads to 5-year progression-free survival (PFS) rates and freedom-from-treatment failure (FFTF) rates of 70-85%, regardless of the chemotherapy regimen applied. Patients with HL experiencing disease progression during or within 3 months of front-line therapy (primary refractory) and patients whose disease relapses after a complete response have a second chance of treatment. The standard of care for relapsed or refractory HL is second-line chemotherapy followed by autologous stem cell transplantation (ASCT), which can induce long-term remission in approximately 40-50% of patients. However, HL recurrence occurs in about 50% of patients after ASCT, usually within the first year, and represents a significant therapeutic challenge. Allogeneic transplantation from HLA-matched donors represents the standard of care for patients with HL relapsing after- or refractory to ASCT.

Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in the Era of Tyrosine Kinase Inhibitors: A Registry-Based Study of the Italian Blood and Marrow Transplantation Society (GITMO).

We performed a nationwide registry-based analysis to describe the clinical outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who underwent an allogeneic hematopoietic stem cell transplantation (HSCT) after a tyrosine kinase inhibitor (TKI)-based treatment A total of 441 patients were included in the study. The median age at HSCT was 44 years (range, 18 to 70 years). All 441 patients (100%) received TKI before HSCT (performed between 2005 and 2016). Of these 441 patients, 404 (92%) were in cytologic complete remission (CR), whereas the remaining 37 (8%) had active disease at the time of HSCT. Molecular minimal residual disease (MRD) was negative in 147 patients (36%) at the time of HSCT. The donor was unrelated in 46% of patients. The most prevalent source of stem cells was peripheral blood (70%). The conditioning regimen was myeloablative in 82% of cases (total body irradiation-based in 50%) and included antithymocyte globulin in 51% of patients. With a median follow-up after HSCT of 39.4 months (range, 1 to 145 months), the probability of overall survival (OS) at 1, 2, and 5 years was 69.6%, 61.1% and 50.3%, respectively, with a median OS of 62 months. Progression-free survival (PFS) at 1, 2, and 5 years was 60.2%, 52.1% and 43.7%, respectively. OS and PFS were significantly better in patients who were in CR and MRD-negative at the time of HSCT compared with patients who were in CR but MRD-positive (50% OS not reached versus 36 months; P = .015; 50% PFS not reached versus 26 months, P = .003). The subgroup of MRD-negative patients both at HSCT and at 3 months after HSCT had a better outcome (5-year OS, 70%). Conversely, the 37 patients who underwent a HSCT with active Ph+ ALL had a median OS of 7 months and a median PFS of 5 months. The 5-year cumulative incidence of relapse was significantly lower in MRD-negative patients (19.5% versus 35.4%; P = .001). Nonrelapse mortality (NRM) after 1, 2, and 5 years was 19.1% (95% confidence interval [CI], 15.5% to 22.9%), 20.7% (95% CI, 17% to 24.7%), and 24.1% (95% CI, 20% to 28.5%), respectively. NRM was significantly lower with a modified European Society for Blood and Marrow Transplantation (mEBMT) risk score of 0 to 2 compared with ≥3 (15% versus 25%; P = .016). The median OS for Ph+ ALL patients who underwent a TKI-based treatment followed by an allogeneic HSCT, in recent years at the GITMO centers, was 62 months. Evaluation of the mEBMT risk score can be useful to predict NRM. Our data confirm that HSCT is a potentially curative treatment for Ph+ ALL with an excellent outcome for the subgroup of MRD-negative patients both at HSCT and at 3 months after HSCT (5-year OS, 70%).

Acute GVHD prophylaxis plus ATLG after myeloablative allogeneic haemopoietic peripheral blood stem-cell transplantation from HLA-identical siblings in patients with acute myeloid leukaemia in remission: final results of quality of life and long-term outcome analysis of a phase 3 randomised study.

BACKGROUND: We previously showed that human anti-T-lymphocyte globulin (ATLG) plus ciclosporin and methotrexate given to patients with acute leukaemia in remission, having allogeneic haemopoietic stem-cell transplantation with peripheral blood stem cells from an HLA-identical sibling donor after myeloablative conditioning, significantly reduced 2-year chronic graft-versus-host disease (cGVHD) incidence and severity, without increasing disease relapse and infections, and improves cGVHD-free and relapse-free survival (cGRFS). The aim of an extended follow-up study was the assessment of long-term outcomes, which are, in this context, scarcely reported in the literature. We report unpublished data on quality of life (QoL) from the original study and the results of a follow-up extension. METHODS: In the original open-label study, patients with acute myeloid and lymphoblastic leukaemia in first or subsequent remission, having sibling HLA-identical allogeneic peripheral blood stem-cell transplantation, were randomly assigned (1:1) to receive ATLG plus standard GVHD prophylaxis with ciclosporin and short-term methotrexate (ATLG group) or standard GVHD prophylaxis without ATLG (non-ATLG group). Conditioning regimens were cyclophosphamide 120 mg/kg with either total body irradiation (12 Gy) or busulfan (12·8 mg/kg intravenously or 16 mg/kg orally), with or without etoposide (30-60 mg/kg). Randomisation was stratified according to centre and disease risk. The primary endpoint was cumulative incidence of cGVHD at 2 years. The primary and secondary endpoints, excluding QoL, have been published. QoL, assessed using European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-HDC29 questionnaires, was an unpublished secondary endpoint, which we now report here. A follow-up extension was then done, with the primary endpoint cumulative incidence of cGVHD. Enrolment has been completed for both studies. The original trial (number, NCT00678275) and follow-up extension (number, NCT03042676) are registered at ClinicalTrials.gov. FINDINGS: In the original study, from Dec 14, 2006, to Feb 2, 2012, 161 patients were enrolled and 155 were randomly assigned to either the ATLG group (n=83) or to the non-ATLG group (n=72). In the follow-up study, which started on Feb 7, 2017, and was completed on June 30, 2017, 61 patients were included in the ATLG group and 53 were included in the non-ATLG group. Global health status showed a more favourable time course in the ATLG group compared with the non-ATLG group (p=0·02; treatment by visit interaction). ATLG was descriptively superior to non-ATLG at 24 months for physical function (points estimate -14·8 [95% CI -26·4 to -3·1]; p=0·014) and social function (-19·1 [-38·0 to -0·2]; p=0·047), gastrointestinal side-effects (8·8 [2·5-15·1]; p=0·008) and effect on family (13·5 [1·2-25·8]; p=0·032). Extended follow-up (median 5·9 years [IQR 1·7-7·9]) confirmed a lower 5-year cGVHD incidence (30·0% [95% CI 21·4-41·9] vs 69·1% [59·1-80·1]; analysis for entire follow-up, p<0·001), no increase in relapses (35·4% [26·4-47·5] vs 22·5% [14·6-34·7]; p=0·09), improved cGRFS (34·3% [24·2-44·5] vs 13·9% [7·1-22·9]; p=0·005), and fewer patients still in immunosuppression (9·6% vs 28·3%; p=0·017) in the ATLG group compared with the non-ATLG group. 5-year overall survival, relapse-free survival, and non-relapse mortality did not differ significantly between groups. INTERPRETATION: The addition of ATLG to standard GVHD prophylaxis improves the probability of surviving without disease relapse and cGVHD after myeloablative peripheral blood stem-cell transplantation from an HLA-identical sibling donor for patients with acute leukaemia in remission. Further additional benefits are better QoL and shorter immunosuppressive treatment compared with standard GVHD prophylaxis without ATLG. Therefore, in this setting, ATLG plus standard GVHD prophylaxis should be preferred over the standard GVHD prophylaxis alone. FUNDING: Neovii Biotech.

Impact of New Drugs on the Long-Term Follow-Up of Upfront Tandem Autograft-Allograft in Multiple Myeloma.

Before the introduction of "new drugs," we designed a trial in which 162 newly diagnosed myeloma patients were biologically randomized to receive either an autologous stem cell transplant (auto-SCT) followed by a nonmyeloablative allogeneic stem cell transplant (allo-SCT) or a double auto-SCT. Fifty-eight patients in the allo-SCT arm and 46 in the double auto-SCT arm completed the assigned treatment. At a median follow-up of 12.3 years from allo-SCT and 12.1 years from second auto-SCT, median overall survival (OS) was 11.4 in the allo-SCT arm and 3.9 years in the auto-SCT -arm (P = .007), whereas event-free survival was 3.6 and 1.5 years (P < .001), respectively. A subset of allo-SCT patients showed persistent molecular remission. Two-year cumulative incidence of chronic graft-versus-host disease was 67.2%. At 5 years, 39% of these patients were alive, disease-free, and off immunosuppression; 36.6% had relapsed and 12.2% were still on immunosuppression. Thirty-three of 58 patients (allo-SCT arm) and 39 of 46 (auto-SCT arm) relapsed at least once and were rescued with new drugs. In the allo-SCT arm, 2 patients in biochemical relapse did not reach clinical criteria for treatment. Overall 28 (90%) were treated with new drugs and 14 (45%) received donor lymphocyte infusions (DLIs). In 28 of 31 patients (90%) DLIs were given with new drugs. Median OS from first relapse was 7.5 years in the allo-SCT arm and 2 years in the auto-SCT arm (P = .01). Patients who received DLI showed significantly longer OS (hazard ratio, .38; P = .042) as compared with auto-SCT patients. This difference was slightly lower when only allo-SCT patients who did not receive DLIs were considered (hazard ratio, .56; P = .154). In summary, long-term disease-free survival and survival outcomes after treating relapse with new drugs with or without DLIs were better in allo-SCT patients.

Steroid treatment of acute graft-versus-host disease grade I: a randomized trial.

Patients with acute graft-versus-host disease (GvHD) grade I were randomized to an observation arm (n=85) or to a treatment arm (n=86) consisting of 6-methylprednisolone 1 mg/kg/day, after stratification for age and donor type. The primary end point was development of grade II-IV GvHD. The cumulative incidence of grade II-IV GvHD was 50% in the observation arm and 33% in the treatment arm (P=0.005). However, grade III-IV GvHD was comparable (13% vs 10%, respectively; P=0.6), and this was true for sibling and alternative donor transplants. Moderate/severe chronic GvHD was also comparable (17% vs 9%). In multivariate analysis, an early interval between transplant and randomization (

Phase II study of perifosine and sorafenib dual-targeted therapy in patients with relapsed or refractory lymphoproliferative diseases.

PURPOSE: To evaluate safety and activity of perifosine and sorafenib combination therapy in patients with lymphoproliferative diseases. EXPERIMENTAL DESIGN: Patients with relapsed and refractory lymphoproliferative diseases received perifosine (50 mg twice daily) for 1 month. Patients achieving less than partial response (PR) after perifosine alone were administered the combination therapy [perifosine plus sorafenib (400 mg twice daily)] until progressive disease (PD) or unacceptable toxicity occurred. The pERK and pAKT in peripheral blood lymphocytes as well as serum cytokine levels were investigated as predictive biomarkers of response. RESULTS: Forty patients enrolled in this study. After 1 month of perifosine alone, 36 who achieved less than PR went on to combination therapy, whereas four patients with chronic lymphocytic leukemia (CLL) who achieved PR continued with perifosine alone for a median of 10 months (range, 4-21). The most common drug-related toxicities were grade 1-2 anemia (17%), thrombocytopenia (9%), diarrhea (25%), joint pain (22%), and hand-foot skin reaction (25%). Three patients experienced grade 3 pneumonitis. Eight patients (22%) achieved PR, 15 (42%) achieved stable disease, and 13 (36%) experienced PD. A 28% PR rate was recorded for 25 patients with Hodgkin lymphoma. Among all patients, median overall survival and progression-free survival were 16 and 5 months, respectively. Early reductions in pERK and pAKT significantly correlated with the probability of clinical response. CONCLUSIONS: Perifosine and sorafenib combination therapy is feasible with manageable toxicity and demonstrates promising activity in patients with Hodgkin lymphoma. The predictive value of pERK and pAKT should be confirmed in a larger patient cohort.

Peripheral blood CD34+ percentage at hematological recovery after chemotherapy is a good early predictor of harvest: a single-center experience.

Several algorithms for early prediction of poor-mobilizing patients after chemotherapy and granulocyte colony-stimulating factor administration have been proposed. They generally define peripheral blood cut-off levels of CD34+ cells at a fixed day after starting chemotherapy, mostly with cyclophosphamide. To define an algorithm for early addition of plerixafor regardless of the chemotherapy regimen used, we retrospectively analyzed 280 chemomobilization attempts in 236 patients treated at our institution between 2002 and 2012. In multivariate analysis, CD34+ absolute count and CD34+ percentage upon total leukocyte count at day 1 (defined as the first day in which leukocytes reached a value > 1 × 10(9)/L) were the only factors able to predict a total harvest ≥ 2 × 10(6) CD34+/kg. In patients with day 1 CD34+ lower than 20/µL, the CD34+ percentage was a more reliable predictor of stem cell harvest in the following days than CD34+ absolute count. Upon definition of the best CD34+ cut-off value for identification of poor-mobilizing patients, an algorithm was set up to guide plerixafor administration. It was prospectively validated in 20 patients in 2013 with encouraging results in terms of low incidences of both mobilization failure and plerixafor use. Large prospective trials that define the most cost-effective strategy for just-in-time rescue plerixafor are warranted.

Multicenter experience using total lymphoid irradiation and antithymocyte globulin as conditioning for allografting in hematological malignancies.

A non myeloablative conditioning with total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) was shown to protect against graft-versus-host disease (GVHD). To evaluate the effects of TLI-ATG in a multicenter study, 45 heavily pretreated patients, median age 51, with lymphoid (n = 38) and myeloid (n = 7) malignancies were enrolled at 9 centers. Twenty-eight patients (62%) received at least 3 lines of treatment before allografting, and 13 (29%) had refractory/relapsed disease at the time of transplantation. Peripheral blood hematopoietic cells were from HLA identical sibling (n = 30), HLA-matched (n = 9), or 1 antigen HLA-mismatched (n = 6) unrelated donors. A cumulative TLI dose of 8 Gy was administered from day -11 through -1 with ATG at the dose of 1.5 mg/kg/day (from day -11 through -7). GVHD prophylaxis consisted of cyclosporine and mycophenolate mofetil. Donor engraftment was reached in 95% of patients. Grade II to IV acute GVHD (aGVHD) developed in 6 patients (13.3%), and in 2 of these patients, it developed beyond day 100. Incidence of chronic GVHD (cGVHD) was 35.8%. One-year nonrelapse mortality was 9.1%. After a median follow-up of 28 months (range, 3-57 months) from transplantation, median overall survival was not reached, whereas median event-free survival was 20 months. This multicenter experience confirms that TLI-ATG protects against GVHD and maintains graft-vs-tumor effects.

Long-term follow-up of a comparison of nonmyeloablative allografting with autografting for newly diagnosed myeloma.

Before the introduction of new drugs, we designed a trial where treatment of newly diagnosed myeloma patients was based on the presence or absence of HLA-identical siblings. First-line treatments included a cytoreductive autograft followed by a nonmyeloablative allograft or a second melphalan-based autograft. Here, we report long-term clinical outcomes and discuss them in the light of the recent remarkable advancements in the treatment of myeloma. After a median follow-up of 7 years, median overall survival (OS) was not reached (P = .001) and event-free survival (EFS) was 2.8 years (P = .005) for 80 patients with HLA-identical siblings and 4.25 and 2.4 years for 82 without, respectively. Median OS was not reached (P = .02) and EFS was 39 months (P = .02) in the 58 patients who received a nonmyeloablative allograft whereas OS was 5.3 years and EFS 33 months in the 46 who received 2 high-dose melphalan autografts. Among patients who reached complete remission in these 2 cohorts, 53% and 19% are in continuous complete remission. Among relapsed patients rescued with "new drugs," median OS from the start of salvage therapy was not reached and was 1.7 (P = .01) years, respectively. Allografting conferred a long-term survival and disease-free advantage over standard autografting in this comparative study.

Early chemotherapy intensification with BEACOPP in advanced-stage Hodgkin lymphoma patients with a interim-PET positive after two ABVD courses.

UNLABELLED: Interim 2-[18F]Fluoro-2-deoxy-D-glucose Positron Emission Tomography performed after two chemotherapy cycles (PET-2) is the most reliable predictor of treatment outcome in ABVD-treated Hodgkin Lymphoma (HL) patients. We retrospectively analysed the treatment outcome of a therapeutic strategy based on PET-2 results: positive patients switched to BEACOPP, while negative patients continued with ABVD. Between January 2006 and December 2007, 219 newly diagnosed HL patients admitted to nine centres were enrolled; 54 patients, unfit to receive this treatment were excluded from the analysis. PET-2 scans were reviewed by a central panel of nuclear medicine experts, according to the Deauville score (Meignan, 2009). After a median follow up of 34 months (12-52) the 2-year failure free survival (FFS) and overall survival for the entire cohort of 165 patients were 88% and 98%; the FFS was 65% for PET-2 positive and 92% for PET-2 negative patients. For 154 patients in which treatment was correctly given according to PET-2 review, the 2-year FFS was 91%: 62% for PET-2 positive and 95% for PET-2 negative patients. CONCLUSIONS: this strategy, with BEACOPP intensification only in PET-2 positive patients, showed better results than ABVD-treated historic controls, sparing BEACOPP toxicity to the majority of patients.