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8038 Background: Novel salvage therapies for relapsed/refractory (r/r) DLBCL and the identification of specific biomarkers predictive of response to a specific therapy are needed. L has an overall response rate (ORR) of 28% in r/r DLBCL. Methods: We retrospectively evaluated differences in clinical outcomes for germinal center B-cell (GCB)-like vs non-GCB-like DLBCL patients treated with salvage L alone (RPCI) or L+R (DHOS-S). We are augmenting the current database with pathology specimens from r/r DLBCL patients treated with L monotherapy at the Mayo Clinic and Hackensack Cancer Center. The initial data set from RPCI included 18 patients with r/r large cell lymphoma: 8M/10F; median age: 64 yrs; median 4 prior treatments. Patients were classified as GCB (n=9) or non-GCB (n=9) using the Hans criteria. Differences in overall response rate (ORR), CR or PR rates, progression-free survival (PFS), and overall survival (OS) were compared between GCB and non-GCB DLBCL. Results: No differences in stage, internatio...

8037 Background: From time of diagnosis, patients with indolent lymphoma have a 10-year 30% risk of transformation to an aggressive non-Hodgkin's lymphoma (aNHL) (Al-Tourah. JCO. 2008). Patients wi...

Fourty-four evaluable patients with hairy cell leukemia (HCL) were treated with human lymphoblastoid alpha-interferon (alpha-IFN), at a dose of 3 x 10(6) Units a day for 12-18 months while 18 of them continued to receive a three times per week schedule at the same dose as maintenance treatment. Eighteen percent of patients achieved complete response, 64% partial response, and 18% minor response with a median duration of 37.5, 22.9 and 3.5 months respectively. Twenty patients (45%), all partial or minor responders, subsequently had progression of the disease. The progression occurred more frequently in patients who presented at diagnosis with a hairy-cell index value > 0.50 than in those who presented with a hairy-cell index < 0.50: 14/26 (54%) versus 2/11 (18%) respectively. In addition, the progression rate was more evident in "non-maintained" than in "maintained" patients: 16/26 (61.5%) versus 4/18 (22%). Restarting alpha-IFN treatment in 16 of the 20 progressed patients proved effective only in 9 of them. From these findings it appears that a low hairy-cell index at diagnosis correlates favorably with a good hematological response. Furthermore, continuous therapy with alpha-IFN seems very useful in reducing the progression of the disease, in particular in patients with a very high hairy-cell index at diagnosis.

A retrospective analysis on HODGKIN'S DISEASE (HD) was finalized to see if changing the management and therapy during the years we improved the cure rate of lymphomas and reduced the incidence of side effects due to therapy. Up to twenty years' experience was based in two major therapeutic periods: the first included patients observed between 1970 and June 1980 and the second between July 1980 and December 1987. Significant differences between the two periods were the reduction of splenectomies as staging procedure, the reduction of radiation dose and extension and the sequential use of MOPP/ABVD instead of MOPP alone.The analysis included all patients observed over the twenty years under study by looking to the differences concerning response to therapy, survival, relapse-free survival and major consequences due to therapy, namely death not directly related to lymphoma. 377 pts entered the first period and 193 the second one with a minimum follow-up of 4 years.Significant differences were recorded on CR rate, 80.9% vs 90.5%, respectively (p = 0.0024) and deaths in CR, 15.1% vs 2.6%, respectively (p = 0.000). The overall survival shows a probability of 60% and 83% at 11 years for the first and the second group, respectively (p = 0.000) being the probability of survival of 50% at 20 years for the first group of pts. The probability of being in remission is similarly of 79% and 78%, for the first and second group, respectively. The risk of death in remission accounting all causes not related to lymphoma shows a 17% probability vs 6% at 11 years (p = 0.006) for the first and second group, respectively, being 38% for the former group at 20 years. The most frequent single cause of death in remission was secondary leukemia which was recorded in 14 pts on the group of pts observed between 1970 and 1980, all splenectomized and treated by MOPP and extensive radiotherapy.The modifications of therapy of HD have produced improvements concerning the prognosis of pts; these improvements are due mainly to the reduction of late side effects such as acute leukemia and second solid tumor, and to the increase of remission rate and cure rate of the lymphoma.

In the past several decades, scientific and therapeutic advances have transformed Hodgkin's disease from a uniformly fatal illness to one that can be treated with the expectation of long-term remission or cure in the majority of cases. Because patients now survive for long periods after treatment, various late complications are being identified. Among patients with such late complications, some have been reported to experience "very late" relapses (10 years). Here we document recurrences in three patients with Hodgkin's disease more than 10 years after remission.

This study was designed to evaluate the therapeutic efficacy and toxicity of recombinant interferon alpha-2a (rIFN alfa-2a) given as initial systemic therapy in untreated mycosis fungoides and/or Sezary's syndrome patients, at a slowly escalating schedule up to the maximal tolerated dose. At the same time this schedule was administered in patients who had relapsed or were refractory to previous treatment; 28 newly diagnosed and 15 previously treated patients entered the study. IFN was given daily with dose escalation from 3 to 18 MU. The last follow-up in June 1990 indicates that 90% of previously untreated patients who obtained a complete remission remain in continuous complete remission after 18 to 40 months and that 75% of previously untreated patients who obtained partial remission remain in partial remission after 20-44 months. The event-free survival projected, calculated using the Kaplan and Meier product limit technique, was 21% of all patients at 54.7 months (40% in the previously untreated groups and 14% in the previously treated group: P = 0.12). In conclusion, interferon is very effective as a single agent in cutaneous T-cell lymphomas.

Following irradiation alone, secondary acute leukemia is extremely uncommon; following chemotherapy alone, the risk is increased, but not as much as when continued maintenance chemotherapy or combined modality treatments are used.The risk of secondary acute nonlymphocytic leukemia (ANLL) was assessed in 552 patients with Hodgkin's disease (HD), who were diagnosed at the Hematology Institute of Bologna from 1970 through 1984 and followed-up through July, 1990. Median follow-up time was 12 years.ANLL developed in 14 of 328 patients treated with the combined modality of extended-field radiotherapy (RT) plus chemotherapy (CT). All ANLL was observed in patients who had received the mechlorethamine-vincristine-procarbazione-prednisone (MOPP) regimen. No ANLL was documented among 115 patients treated with RT alone, nor among the 109 given CT alone. Leukemia, which developed 34-184 months after diagnosis of HD, was always preceded by a preleukemic phase and was fatal (after 1-12 months) to 13 patients. The karyotype of the leukemia cells was studied in 11 of the 14 patients and was always abnormal.A Cox's Linear Logistic Model that was performed did not demonstrate that the treatment categories, age, sex, and splenectomy were prognostic factors. Because all ANLL was observed in patients who were treated with extended-field RT plus MOPP and who had undergone splenectomies at diagnosis of HD, further research with larger numbers of patients and longer follow-up should be pursued. Thus with such additional data, clinicians could come to appreciate fully the statistical significance of our interesting observations.

From February, 1987 to August, 1988, fifty-one patients with high and intermediate grade non-Hodgkin's lymphoma (NHL) entered a chemotherapy program MNCOP-B (M = Methotrexate, N = Novantrone, C = Cytoxan, O = Oncovin, P = 6 methyl-prednisolone, B = Bleomycin). Forty patients received MNCOP-B as first-line therapy and 11 patients as salvage therapy after relapse-resistance to other schemes or radiotherapy.The overall remission rate was 51% with a similar distribution of remissions between the two groups under study. At a mean follow-up of 28 months, 20 patients (40%) remain in CR with a disease-free probability of 83% for patients treated with MNCOP-B as up-front therapy and 67% for patients treated with MNCOP-B as salvage therapy. The overall survival at 3 years is 45%; bulky, disease stages III-IV and symptoms are not correlated with poorer survival or a lower remission rate. Patients who received less than 70% of the scheduled doses paradoxically figure better than the others, showing an 87% remission rate, as compared to those who received 100% of the scheduled doses and obtained a 35% remission rate. Major toxicity consisted of mucositis, recorded in 15% and 9% of previously untreated and treated patients, respectively; severe neutropenia was recorded in 27% and 63%, respectively. Despite the number of recorded side effects, only one toxic death due to sepsis occurred.MNCOP-B is an effective regimen in intermediate and high grade NHL and easily manageable in the out-patient clinic. The incidence of mucositis is sensibly reduced as compared to the parental regimen MACOP-B reported in the literature; this result allows the use of MNCOP-B in older patients.

The treatment strategy for stage I non-Hodgkin's lymphomas (NHL) is far from being clearly established.Thirty-seven patients (pts) with clinical stage I high-grade NHL treated between 1983 and 1989 have been retrospectively reviewed. Nineteen pts were treated by radiotherapy (RT) alone; 14 pts received chemotherapy (CT) followed by adjuvant RT, 3 pts CT alone and 1 pt underwent surgery alone. All pts with bulky disease were submitted to combined therapy.Estimated 7-yr overall survival (OS) was 82%, while freedom from relapse (FFR) was 73%. No differences in OS and FFR were recorded with regard to the type of treatment, site of the tumor, sex or histology.Our conclusion is that stage I NHL, even with unfavourable histology, may be successfully treated with RT only; however, CT before RT may be recommended in pts with a higher risk of relapse, i.e. the presence of bulky mass.

Background. Peripheral T-cell lymphoma not otherwise specified (PTCL/NOS) is the most common T-cell lymphoma; however, it remains a complex entity showing great variety regarding morphology, immunophenotype and clinical behaviour. Recently, gene expression profiling (GEP) revealed PDGFRA as possible PTCL-associated molecule, by nominating it as potential therapeutic target. Aims and Methods. We investigated the possible determinants of PDGFRA activity in PTCL/NOS. We performed GEP of 28 PTCLs/NOS and 20 samples of normal T-cell subpopulations, by using the Affymetrix HG-U133 2.0 plus microarray. Moreover, we built tissue-microarrays (TMAs) including 145 PTCLs/NOS for protein analyses. The PDGFRA locus (4q1.1–4q1.3) was studied by FISH on those TMAs, while direct sequencing of all PDGFRA exon and introns as well as of the promoter region was performed in 90 cases. Immunohistochemistry (IHC) and ELISA were adopted in order to study the expression of PDGF-A, PDGF-B and PDGF-C on tissue sections and in supernatants from PTCL/NOS cell cultures, respectively. Finally, the expression of PDGFRA and its activated (phosphorilated) form, p-PDGFRA, was assessed by IHC on TMAs, and by flow-citometry in PTCL/NOS cultured cells before and after the exposure to an anti-PDGF ligand neutralizing antibody (R&B System). Results. First, GEP showed over-expression of PDGFRA in all tested PTCLs/NOS, while IHC confirmed the expression of PDGFRA and p-PDGFRA. FISH, SNPs analysis and direct sequencing showed preserved integrity of PDGRA locus. We then studied PDGF-A, PDGF-B and PDGF-C, which turned out to be expressed and secreted by PTCL/NOS cells. In order to verify the hypothesis of an autocrine loop, we tested whether the remotion of PDGF ligands from the supernatants of cultured PTCL/NOS cells determined PDGFRA de-phosphorilation. Notably, 48h after the exposure to 20 mg of anti-PDGF antibody, we already appreciated a significant effect with reduction of PDGFRA phosphorilation up to 75%. Conclusions. Taken together, our data demonstrate that PDGFRA activity is sustained by an autocrine loop in PTCL/NOS.

Background: Autologous stem cell transplantation produces prolonged disease free survival in patients with relapsed or refractory Non Hodgkins Lymphoma (NHL), although relapse remains the most common cause of treatment failure. Radioimmunotherapy (RIT) is a novel treatment option for NHL patients combining immunotherapy and radiation. However, there are only sparse data available on the safety and efficacy of radioimmunotherapy for relapse after autologous stem cell transplantation (ASCT). Methods: The RIT-Network, started in December 2006, is a web-based, international registry that collects real-world, observational data from RIT-treated patients (pts) with malignant lymphoma from across the world. To date, data of 680 pts treated with RIT have been entered into the database. 78 pts who have received RIT (primarily ibritumomab tiuxetan) following a stem cell transplantation are documented in the registry, 50 pts with follicular lymphoma (FL) and 28 pts. with other histologies. 62 pts with a follow up of > 12 months are included in the following analysis. Results: 62 pts (42 with and 20 with other histologies: 2pts. B - CLL, 10 pts. DLBCL, 1pt. lymphoplasmacytic, 5pts. mantle cell, 2 pts. nodal marginal) are included in the analysis. Median age at primary diagnosis was 48 years (range 23 to 68 yrs). Tumor stage showed 3 pts. stage I, 7 pts. stage II, 19 pts stage III, 32 pts. stage IV, for 1 pt. tumor stage is not 1 documented. 40 % of the pts. had previous radiotherapy, 48% of the pts. 1–3 previous Ctx., 45% 4–6 previous Ctx. and 7% had more than 7 previous Ctx. 57 pts. had one previous ASCT and 4 pts. had 2 previous ASCTs. 8 patients had already undergone RIT previously. RIT was used as second line therapy in 6 pts., third line in 13 pts., fourth line in 15 pts., fifth line in 18 pts. and > sixth line in 6 pts. The indication for most of the patients was recurrence (31 pts.) consolidation (13 pts.) and therapy refractory (11 pts.). Best response was CR in 21 pts (34%), PR in 15 pts. (24%), SD in 3 pts (5%) and PD in 13 pts. (21%). Haematotoxicity is not documented for all patients. Median nadir for haemoglobin (Hb) (n=46), neutrophils (ANC) (n=40) and platelets (plts) (n=47) was 8.95 g/dl (range 4.1 to 15.1g/dl), 1,3/μl (range 0–2290 ANC/μl) and 89 μl (range 8 – 150 000 tplst/μl) respectively. Time to nadir was 49 (range 1 to 400), 45 (range 13–412) and 34 (range 14 to 404) days for Hb, neutrophils and plts, respectively. Complete recovery of blood count was reached in median on day 133 (range day 28–467 days). Conclusion: RIT is a feasible and safe treatment modality for patients who relapsed after autologous stem cell transplantation for relapsed or refractory NHL. RIT shows encouraging results with a CR rate of 34% in this non-interventional registry analysis. Haematotoxicity seems to be increased in comparison to first- or second line RIT. Prospective clinical trials in this patient population are warranted.

Alpha-interferon (alpha-IFN) treatment is highly effective in normalizing the clinical, hematologic, and immunologic parameters of patients with hairy cell leukemia (HCL). Complete remissions (CR), however, are rare, and a few patients do not respond adequately to alpha-IFN. That the poor response to alpha-IFN treatment could be related to a particular immunologic surface marker profile of the HC was investigated in this study. The results showed that most patients who do not respond adequately to alpha-IFN HC have a peculiar immunologic phenotype with a positive response to the Leu1 (CD5) monoclonal antibody, usually absent on HC but characteristically expressed on B-chronic lymphocytic leukemia cells. Of nine HCL patients with this phenotype, only three had partial remissions (PR) and six minor responses (MR) compared with the three CR, 16 PR, and three MR observed in the 22 Leu1 (CD5)-negative patients. The authors postulate that a more extensive immunologic analysis of HCL patients at diagnosis may be predictive of the response to IFN treatment.

8053 Purpose: To determine the impact of MTS in young (18 to 60 years) patients with DLBCL and aaIPI=0,1. Patients and Methods: Outcome of patients treated with CHOP-like chemotherapy with (R-CHEMO) or without rituximab (CHEMO) was analyzed according to MTS. Results: A Martingale residual analysis revealed a linear negative prognostic impact of MTS on event-free (EFS) and overall (OS) survival. The hazard ratios for MTS per centimeter increase were significant for EFS (1.07; 95%-CI: 1.04–1.11; p10cm. R-CHEMO 3-year EFS ranged from 83% (MTS =10cm). CHEMO 3-year OS rates decreased from 93% (MTS =10cm). R-CHEMO 3-year OS decreased from 98% (MTS =10cm). With CHEMO, any cut-off point between 5 and 10 cm separated a thus defined “non-bulky” from a “bulky” population with a 3-year EFS difference >20% (p12% (p=10cm separated two populations with a significant EFS difference (9.1%; p=0.047), and cut-off points >=6cm discriminated two populations with a significant OS difference (7.6%-11.3%; p=0.037–0.0009). Conclusion: Due to the linear prognostic impact of MTS on outcome, cut-off points for “bulky” disease can be set rather arbitrarily between 5 and 10cm depending on clinical considerations. Rituximab reduces, but does not eliminate the negative prognostic impact of MTS in young patients with good-prognosis DLBCL. [Table: see text]

6529 Background: The addition of rituximab (R) to 6 cycles of CHOP-like regimens in the MInT trial significantly improved overall results and set a new standard in young good-prognosis patients with DLBCL (Blood 2004,104:48a). As CHOEP-21 had been shown to be superior to CHOP-21 without R (NHL-B1 trial; Blood 2004, 104:626), we investigated whether these differences could be confirmed in the MInT trial where participating countries selected 1 of 4 CHOP-like regimens. Methods: Intent-to-treat-analysis of the primary endpoint time-to-treatment-failure (TTF) and the secondary endpoints complete remission (CR) rate and overall survival (OS) of different regimens with or without rituximab. Results: Of 823 evaluable patients, 48% (197/199) were randomized to CHOP-21±R, 44% (180/181) to CHOEP±R, 4% (17/17) to MACOP-B±R and 4% to (16/16) PMitCEBO. All regimens were well balanced for prognostic factors, except for MACOP-B±R with more favorable patients. Numbers for MACOP-B and PMitCEBO are too small for meaningful...

6500 Background: While rituximab improved outcome in elderly patients with DLBCL (Coiffier et al., 2002), there is no data for young low-risk patients. Methods: In a randomized study conducted in 18 countries, untreated patients (18–60 years) with low-risk DLBCL (IPI 0 or 1, stages II-IV and stage I with bulk) were randomized to 6 cycles of a CHOP-like regimen (CHEMO) or the same chemotherapy plus rituximab 375 mg/m2 given on days 1, 22, 43, 64, 85, and 106 (R-CHEMO). Radiotherapy was planned to initial bulk and/or extranodal involvement. The primary endpoint was time to treatment failure (TTF) with events defined as failure to achieve complete remission, progressive disease, relapse, or death. The trial was powered to show a 10% difference in TTF rate after 3 years. Results: Between 05/2000 and 10/2003, 824 patients were recruited. The first planned interim analysis was performed on 326 evaluable patients with confirmed CD20 positive DLBCL (median age 48 years; IPI=1: 56%, 24% stage III/IV disease, 32% e...

We have read with interest the eletter by Dr Naresh dated 26 March1 in response to our earlier review.2 This letter dealt with the problem of the borders between classic Hodgkin’s lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) and suggested that the proponents of the World Health Organisation (WHO) classification had a more flexible attitude towards cHL than ALCL.3 We believe that the WHO classification simply reflects the philosophy of the revised European–American (REAL) classification of lymphoid neoplasms, by drawing up a list of entities that can be readily recognised with the techniques available at the moment, which are defined by the amalgamation of cell morphology, phenotype, cytogenetics, molecular data, and clinical findings.4 This list can be easily updated, whenever new validated information becomes available in the literature. We believe that the present scenario of cHL is much more homogeneous than the one depicted for ALCL. In fact, most if not all examples of cHL have a germinal centre cell derivation, as shown by molecular data and B cell specific activator protein (BSAP) expression,5 with cases of T cell origin being exceptional and still a matter of speculation.2 In …

Twenty-three patients with hairy-cell leukaemia (HCL), six of whom were previously splenectomized, were treated with α-interferon (α-IFN) 3 MU per day for 3–6 months and then with 3 MU three times per week for at least 3 further months. Seven patients (two splenectomized) showed a complete response (CR), 11 patients achieved a partial response (PR) and the remaining five experienced only a minor response (MR). All seven patients who achieved a CR are still in CR after 10–21 months from the onset of the disease. Among the 11 PRs, five showed an increase in the number of circulating hairy cells during the follow-up; they were re-started on α-IFN and an improvement of the haematological values was again obtained. One patient who achieved only a MR died after 1 month therapy because of severe infection. Following treatment with α-IFN, the improvement or normalization of the peripheral blood counts was paralleled by an improvement of the immunologic surface markers, as determined by monoclonal antibodies, and by an improvement of the response to PHA and of the natural killer activity. These findings, coupled to the mild drug-related toxicity observed, confirm that treatment with α-IFN represents a safe and effective therapeutic approach for both splenectomized and non-splenectomized HCL patients.

The main purpose of this work is to give methodologic details and further verification regarding the predictive system recently elaborated for Hodgkin's disease (HD) patients, by which, under standard accuracy and conventional treatment, patient survival can be directly estimated (within a given confidence interval) when six of the best prognostic factors are suitable computed. The factors are, in decreasing order of importance, erythrocyte sedimentation rate (ESR), clinical stage, histologic subtype, age, serum albumin and sex. They were selected on the basis of a multivariate analysis applied to the exponential model for survival time distribution that proved to fit the original data from 586 HD patients accurately. A linear equation with these six variables was elaborated to calculate the estimated mean (or median) survival time or the estimated probability of surviving a given time. In the present work the validity of that estimate was successfully checked on a new external group of 261 patients, observed at the University of Bologna. Staging and treatment of these patients were similar to those in the Pavia series, the only exception being the combined radiochemoterapeutic treatment in patients presenting the nodular sclerosis histologic subtype and early clinical stage. A very good agreement was found between estimated survival (according to the Pavia data) and observed survival (in the Bologna series) for patients with any combination of the six prognostic factors, except those including nodular sclerosis and early stage. In these patients the observed survival exceeded that expected. These results demonstrate that (a) the choice of the six prognostic factors and the statistical weight allotted them were correct, and (b) the predictive system is sensitive to effective therapy modifications, which can be identified even in selected patient subsets of a general series. Thus, this prognostic equation can really be a powerful tool in clinical HD research. Explicative notes for the correct use of the predictive equation, together with an example, are reported in the Appendix.

Twenty-three patients with hairy-cell leukaemia (HCL), six of whom were previously splenectomized, were treated with alpha-interferon (alpha-IFN) 3 MU per day for 3-6 months and then with 3 MU three times per week for at least 3 further months. Seven patients (two splenectomized) showed a complete response (CR), 11 patients achieved a partial response (PR) and the remaining five experienced only a minor response (MR). All seven patients who achieved a CR are still in CR after 10-21 months from the onset of the disease. Among the 11 PRs, five showed an increase in the number of circulating hairy cells during the follow-up; they were re-started on alpha-IFN and an improvement of the haematological values was again obtained. One patient who achieved only a MR died after 1 month therapy because of severe infection. Following treatment with alpha-IFN, the improvement or normalization of the peripheral blood counts was paralleled by an improvement of the immunologic surface markers, as determined by monoclonal antibodies, and by an improvement of the response to PHA and of the natural killer activity. These findings, coupled to the mild drug-related toxicity observed, confirm that treatment with alpha-IFN represents a safe and effective therapeutic approach for both splenectomized and non-splenectomized HCL patients.

In 10 HCL patients, who following treatment for more than 1 year with alpha-IFN, had achieved a normalization of the splenomegaly and a disappearance of circulating hairy cells together with a complete restoration of all peripheral hematological values, a multiple assessment of the apparent complete remission (CR) was carried out. The presence of residual disease was investigated by bone marrow histology, bone marrow immunohistochemistry, immunoglobulin (Ig) gene analysis and on the basis of the serum levels of the soluble form of the Interleukin-2 receptor (sIL-2R). Examination of bone marrow biopsies showed a pattern of CR in 5 cases; 4 of them revealed no evidence of Ig heavy chain gene rearrangement, as well as a near normalization of the serum levels of sIL-2R. Immunohistochemical studies were carried out on embedded paraffin sections with the monoclonal antibody 4KB5 (CD45R) and were assessable in 4 of the 5 patients considered in CR and in 3 of the 4 cases with no Ig gene rearrangement. In 2 the pattern of CR was confirmed, while in the 3rd a minimal but persistent disease (5%) was suspected.

7514 Background: The Fc-enhanced CD19 antibody MOR208 and the immunomodulatory drug LEN have demonstrated single agent activity in patients (pts) with R-R DLBCL. MOR208 and LEN have shown synergy in vitro and in vivo in preclinical lymphoma models. This ongoing phase II study assesses the safety and efficacy of MOR208 + LEN in pts with R-R DLBCL. Methods: Pts >18 years old with R-R DLBCL, ECOG 0–2, adequate organ function, having previously received ≥1 but not more than 3 prior therapies, including ≥1 CD20-targeting regimen and who are not candidates for autologous stem cell transplant (ASCT), are eligible. Treatment comprises up to 12, 28-day (d) cycles (C) of MOR208 12 mg/kg IV, weekly during C1–3 (loading dose d4 of C1); every second week C4–12 + LEN 25 mg po d1–21, C1–12. Pts progression-free after 12 cycles receive up to 12 additional cycles of MOR208 (every second week). The primary endpoint is the overall response rate (ORR) by central radiology assessment. Secondary endpoints include disease control, duration of response, progression-free and overall survival, safety, and response by cell of origin and other biomarkers. A preplanned safety evaluation was undertaken. Results: 31 of 80 planned pts were enrolled prior to data cutoff (3 January 2017). Median age was 74 years (range 47–82); 45% of pts received ≥2 prior lines of therapy; 23% had rituximab refractory disease; 74% had Ann Arbor stage ≥III disease; 65% had elevated lactate dehydrogenase level, and 52% had a poor revised International Prognostic Index (3-5). The most common treatment-emergent adverse events (any grade/grade ≥3 [% pts]) were neutropenia (39/26), anemia (23/0) thrombocytopenia (16/6), infections (26/10) diarrhea (13/0), pyrexia (13/0), and rashes (13/6). Of 26 response evaluable pts (median follow-up 3.3 months), ORR (investigator assessed) was 58% (15 pts), with 7 (27%) complete responses. Median time to response was 1.8 months. Conclusions: The combination of MOR208 + LEN is well tolerated and shows promising activity in pts with R-R DLBCL. Accrual and follow-up of pts is ongoing, as are cell of origin and other biomarker analyses. Clinical trial information: NCT02399085.

Presently, there is no standard second-line regimen for patients (pts) with diffuse large B-cell lymphoma (DLBCL) who cannot undergo stem cell transplantation. Since yttrium-90 (90Y) ibritumomab tiuxetan (Zevalin) is highly active in pts with follicular lymphoma, we wished to establish whether it is also effective in pts with relapsed DLBCL. We therefore conducted a prospective, single-arm, open-label, non-randomized, multicenter phase II trial to evaluate the efficacy and safety of 90Y ibritumomab tiuxetan in elderly pts with histologically confirmed first relapsed or primary refractory DLBCL not appropriate for autologous stem cell transplantation. Pts were divided into 2 groups: those previously treated with chemotherapy alone [Group A, n=76], and those previously treated with chemotherapy and rituximab [Group B, n=28]. Pts in Group A were further divided into 3 strata: pts with primary refractory disease (stratum 1, n= 33), pts relapsing within a year from presentation (stratum 2, n=10), and those relapsing more than 1 year from presentation (stratum 3, n=33). All pts were to receive a single dose of 90Y ibritumomab tiuxetan 14.8 MBq/kg (0.4 mCi/kg) up to a maximum dose of 1184 MBq (32 mCi). The primary endpoint was overall response (ORR) assessed by using IWNHL criteria at Weeks 6, 12, and 24. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). 104 pts were included. Three pts progressed after the first rituximab dose and in 1 patient the 111In labeling procedure failed; 103 pts were evaluable for efficacy and 104 for safety. An ORR of 44% was observed in the entire study population. In Group A, the ORR was 52% in stratum 1, 40% in stratum 2, 58% in stratum 3. In Group B, where 37% of pts were refractory to CHOP-rituximab, the ORR was 19%. The median PFS was 5.9, 2.3, and 6.2 months in strata 1, 2, 3 of Group A, respectively; the median PFS for Group B was 1.6 months. Median OS in Group A was 22.4 months in stratum 3 and has not yet been reached at a maximum follow-up time of 32 months in strata 1&2. Median OS was 4.5 months for Group B. Adverse events (AEs) with the exception of hematologic AEs were generally mild or moderate (CTC grade 1 and 2). There were 4 deaths due to SAEs. Three pts died of suspected cerebral hemorrhage, preceded by CTC grade 4 thrombocytopenias; another died of bleeding from a duodenal ulcer 280 days after the start of study medication, but this AE was determined not to be related to the study drug. The incidence of severe infection is low with 7% of pts hospitalized for infection during the study. In conclusion, 90Y ibritumomab tiuxetan has useful activity in the treatment of relapsed/refractory DLBCL, with no unexpected toxicities observed. The results of this study support a further evaluation of 90Y ibritumomab tiuxetan in combination with chemotherapy or immuno-chemotherapy earlier in the time course of DLBCL.

This retrospective study included 246 patients with a new diagnosis of Hodgkin Lymphoma (HL) with a localized-stage (IA-IIA), consecutively admitted from January 2002 to December 2008, by twelve Italian hematological centers on behalf of Fondazione Italiana Linfomi (FIL). Patients were staged at baseline and after two cycles of chemotherapy with PET. All patients were treated with four cycles of ABVD followed by involved-field radiotherapy. No treatment change, based on PET-2 results was allowed. Endpoint of the study was the predictive role of PET-2 on 2-y failure-free survival (FFS). PET-2 was positive in 36 patients (15%) and negative in 210. After a mean follow-up of 46 (3–105) months 19/36 PET-2 positive patients progressed or relapsed and 17 achieved and maintained a CCR. The positive and negative predictive value of a PET2 was 53% and 95%, respectively. The sensibility, specificity and accuracy of PET2 were 65.5%, 92% and 89%, respectively. PET-2 positive scans were centrally reviewed according to the recently defined Deauville Criteria. Upon review the PPV and NPV was 73% and 96% overall. Factors with prognostic significance for progression in univariate analysis were a positive PET-2 (P = 0.000) and the presence of bulky disease (P

Very few reliable clinical data about the use of radioimmunotherapy in aggressive B-cell lymphoma exist. Patients with aggressive B-cell lymphoma registered in the international RIT-Network were analysed with regard to prior treatment, response and side effects. The RIT-Network is a web-based registry that collects observational data from radioimmunotherapy-treated patients with malignant lymphoma across 13 countries. This analysis included 215 with aggressive B-cell lymphoma out of 232 patients registered in the RIT-Network. Histological subtypes were as follows: 190 diffuse large B-cell, 15 primary mediastinal, 9 anaplastic large cell, and 1 intravascular lymphoma. The median age of the patients was 62 years (range 17 – 88), with 27 % above the age of 70 years. Radioimmunotherapy was mainly used as consolidation after first-line or second-line chemotherapy (56.1 %), as part of third-line to eighth-line therapy for relapse (16.4 %), and in refractory disease (12.2 %). Grade IV neutropenia and thrombopenia and grade III anaemia were observed. The median time to recovery of blood count was 81 days (range 0 – 600 days). The overall response rate was 63.3 %. The complete response rate was 76.4 % in patients treated as part of first-line therapy, and 44.3 % in patients with relapse. Mean overall survival in first-line therapy patients was 32.7 months and 14.0 months in patients with relapse or refractory disease, respectively. Most patients with aggressive B-cell lymphoma in the RIT-Network received radioimmunotherapy as consolidation after first-line therapy with excellent complete remission and overall survival rates compared to published data. In relapsed aggressive B-cell lymphoma, radioimmunotherapy is a safe and feasible treatment leading to satisfactory response rates with acceptable toxicity.

The International Extranodal Lymphoma Study Group coordinated a phase II trial to evaluate the activity and safety of everolimus in marginal zone lymphomas (MZLs). Thirty patients with relapsed/refractory MZLs received everolimus for six cycles or until dose-limiting toxicity or progression. Median age was 71 years (range, 51-88 years). Twenty patients had extranodal, six splenic, four nodal MZL. Twenty-four patients had stage III-IV. Median number of prior therapies was two (range 1-5). Seventeen patients had early treatment discontinuation, in most cases due to toxicity. Median number of cycles was 4.5 (range, 1-16). Among the 24 assessable patients, the overall response rate (ORR) was 25% (95% confidence interval: 10-47). Grade 3-4 adverse events were neutropenia and thrombocytopenia (17% of patients, each), infections (17%), mucositis and odontogenic infections (13%) and lung toxicity (3%). The median response duration was 6.8 months (range, 1.4-11.1+). After a median follow-up of 14.5 months, five deaths were reported: four deaths were due to lymphoma, one was due to toxicity. In an intent-to-treat analysis, the projected median progression-free survival was 14 months. The moderate antitumour activity of everolimus in relapsed/refractory MZLs and the observed toxicity limit its therapeutical applicability in these indolent entities. Lower doses of the drug and, perhaps, different strategies including combination with additional agents need to be explored.

Bendamustine is a bifunctional molecule with both alkylating and antimetabolite properties, synthesized in 1963 by Ozegowski and Krebs in East Germany (German Democratic Republic). Widely used in Eastern Europe for lymphoma and myeloma therapy during the 1970s and 1980s, bendamustine was not studied in well-designed clinical trials until the 2000s. Unique among other recently developed antineoplastic drugs, bendamustine shows high activity and is now approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), being part of the therapeutic armamentarium in indolent and aggressive B-cell non-Hodgkin lymphomas (NHLs), chronic lymphocytic leukemia (CLL), Hodgkin lymphoma (HL) and multiple myeloma (MM). "Bendamustine: role and clinical evidence in lymphoma therapy" is the title of a workshop which took place in Bologna, Italy, on 28 January 2013. This meeting focused on the development, mechanisms of action and evidence supporting the use of bendamustine in lymphoma therapy. This report summarizes the drug development steps, mechanisms of action, clinical results and rationale of use of bendamustine in different lymphoma subtypes, as discussed during the meeting, with the aim of helping the clinician regarding optimal use of this compound in a wide spectrum of lymphoproliferative disorders.

No abstract available.

Regarding primary mediastinal large B-cell lymphoma (PMLBCL), there are several controversial topics that warrant further investigation: the superiority of third-generation regimens, the impact of rituximab, the use of involved field radiotherapy (RT) and the assessment of clinical response by positron emission tomography (PET). We report our experience on 74 PMLBCL patients treated with a combination of a third-generation chemotherapy regimen (MACOP-B) and rituximab: an observational retrospective single-centre study was conducted on patients diagnosed and treated between February 2002 and July 2011. All patients were evaluated by computed tomography scan and PET scan; after the final PET evaluation, PET-negative patients were observed, whereas PET-positive patients underwent mediastinal RT. Sixty-one (82.4\%) patients achieved a complete response after the MACOP-B plus rituximab regimen; 68.9\% presented a positive final PET and were treated with local RT, whereas 31.1\% had a negative PET. Five patients relapsed within 12 months. At 10 years, overall survival was 82\%, progression-free survival was 87.6\% and disease-free survival (DFS) was 90.5\% (median follow-up 4 years). No statistically significant differences were observed in DFS between the patients treated also with RT (PET positive) and patients only observed (PET negative): 90.7\% vs 90\% (p = 0.85), respectively. In our experience, adding rituximab does not change the final results in terms of complete response and DFS utilizing third-generation regimen. Furthermore, the introduction of the PET-guided RT approach leads to a patient-tailored treatment, which preserves the outcome and, at the same time, allows reducing the use of RT. Copyright © 2014 John Wiley & Sons, Ltd.

Standard treatment for patients with Hodgkin lymphoma (HL) unresponsive to upfront therapy or relapsing after primary treatment (RR-HL) consists of salvage chemotherapy followed by autologous stem cell transplant (ASCT). ASCT outcomes are essentially related to two factors: disease burden at the time of transplant and comorbidity status of the patient. Positron emission tomography (PET) scan is a very sensitive diagnostic instrument to measure disease status. In fact, a negative PET status before ASCT is a well-known positive prognostic factor in patients with RR-HL. The recent introduction of the biologically targeted agent brentuximab vedotin has allowed us to treat RR-HL more efficaciously with less toxicity for the patient. Use of this new agent could help achieve a PET-negative status before ASCT in a larger percentage of patients, without severe toxicities, thereby improving ASCT outcomes. Herein we discuss the current evolving scenario of RR-HL treatment.

The International Extranodal Lymphoma Study Group (IELSG) 26 study was designed to evaluate the role of (18)F-fluorodeoxyglucose (18FDG) positron emission tomography/computed tomography (PET/CT) in the management of primary mediastinal (thymic) large B-cell lymphoma (PMBCL). We examined the prognostic impact of functional PET parameters at diagnosis. Metabolic activity defined by the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) was measured on baseline 18FDG PET/CT following a standard protocol in a prospectively enrolled cohort of 103 PMBCL patients. All received combination chemoimmunotherapy with doxorubicin- and rituximab-based regimens; 93 had consolidation radiotherapy. Cutoff values were determined using the receiver-operating characteristic curve. At a median follow-up of 36 months, progression-free survival (PFS) and overall survival (OS) were 87% and 94%, respectively. In univariate analysis, elevated MTV and TLG were significantly associated with worse PFS and OS. Only TLG retained statistical significance for both OS (P = .001) and PFS (P < .001) in multivariate analysis. At 5 years, OS was 100% for patients with low TLG vs 80% for those with high TLG (P = .0001), whereas PFS was 99% vs 64%, respectively (P < .0001). TLG on baseline PET appeared to be a powerful predictor of PMBCL outcomes and warrants further validation as a biomarker. The IELSG 26 study was registered at www.clinicaltrials.gov as #NCT00944567.

Background The optimal treatment of patients with heavily pretreated Hodgkin's lymphoma is controversial. Brentuximab vedotin is an active single agent in this context. Also, bendamustine can be regarded as a safe and effective alternative for patients with relapse after autologous transplantation and as an interesting cytoreductive strategy before allogeneic transplantation. Patients and Methods An observational, multicenter, retrospective study is reported of single-agent bendamustine in 27 heavily pretreated patients with relapsed or refractory Hodgkin's lymphoma, who had all received brentuximab vedotin as their last treatment and who showed disease progression, refractory disease, or early relapse. The primary study endpoint was the objective response rate, and the secondary endpoint was the safety of the bendamustine regimen. Results The overall response rate was 55.5%, with 10 of 27 patients (37.0%) obtaining a complete response. In comparison, the overall response rate previously observed with brentuximab vedotin in the same subset of patients was much lower (18.5%). Among the 10 patients with a complete response after bendamustine, only 1 had had a complete response to brentuximab, with 2 having a partial response and 7 stable or progressive disease. With a median duration of response of 8 months, all these patients had maintained a continuous response at the last follow-up examination. The treatment was well tolerated, with rather infrequent adverse events and transient and manageable toxicities. Conclusion Albeit with the limits of an observational retrospective study, these data indicate that bendamustine shows its efficacy in patients already treated with brentuximab vedotin, regardless of their previously obtained response and without any significant toxicity.

Athracycline-based regimens remain the gold standard for the treatment of lymphomas, even if their use can be limited by associated cardiac toxicity, especially in elderly patients. Although most patients with aggressive non-Hodgkin lymphoma (NHL) are elderly, they may envisage long-term life expectancy. Thus, there is a need for therapeutic strategies that can overcome the impact of anthracycline cardiotoxicity. A better understanding of its pathogenetic mechanisms, the identification of risk factors of cardiac dysfunction, and appropriate therapy should prove useful in this setting. A comparable efficacy and reduced cardiotoxicity even in frail and elderly patients have been shown with the use of non-pegylated liposomal doxorubicin, when substituted for conventional doxorubicin in standard chemotherapy regimens for NHL. In the coming years, the goal will be to apply these advancements to the treatment of patients with NHL, to ensure adequate therapy in patients currently denied conventional intensive chemotherapy because of age or comorbidities.

Purpose Negative [18F]fluorodeoxyglucose (FDG) –positron emission tomography (PET)/computed tomography (CT) after two cycles of chemotherapy indicates a favorable prognosis in Hodgkin lymphoma (HL). We hypothesized that the negative predictive value would be even higher in patients responding rapidly enough to be PET negative after one cycle. This prospective study aimed to assess the prognostic value of PET after one cycle of chemotherapy in HL and to assess the dynamics of FDG uptake after one cycle (PET1) and after two cycles (PET2). Patients and Methods All PET scans were read by two blinded, independent reviewers in different countries, according to the Deauville five-point scale. The main end point was progression-free survival (PFS) after 2 years. Results A total of 126 patients were included, and all had PET1; 89 patients had both PET1 and PET2. The prognostic value of PET1 was statistically significant with respect to both PFS and overall survival. Two-year PFS for PET1-negative and PET1-positive patients was 94.1% and 40.8%, respectively. Among those with both PET1 and PET2, 2-year PFS was 98.3% and 38.5% for PET1-negative and PET1-positive patients and 90.2% and 23.1% for PET2-negative and PET2-positive patients, respectively. No PET1-negative patient was PET2 positive. Conclusion PET after one cycle of chemotherapy is highly prognostic in HL. No other prognostic tool identifies a group of patients with HL with a more favorable outcome than those patients with a negative PET1. In the absence of precise pretherapeutic predictive markers, PET1 is the best method for response-adapted strategies designed to select patients for less intensive treatment.

Brentuximab vedotin was made available via a Named Patient Program (NPP) to non-US/Canadian patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL) or systemic anaplastic large-cell lymphoma (sALCL) until approval in their respective countries. We re-evaluated the efficacy and safety NPP data in a pooled analysis. Through a systematic literature review, 21 NPP publications were identified describing 14 cohorts (N=245). Among patients with a specified diagnosis, 207 had HL, 28 had ALCL, and one had CD30+ T-cell lymphoma (not specified). In cohorts reporting response, overall response and complete remission rates were 67\% and 26\%, respectively, in R/R HL, and 75\% and 74\%, respectively, in R/R ALCL. Incidences of grade 3/4 neurologic and hematologic toxicities were 6\% and 12\%, respectively; 5\% of patients discontinued because of toxicity. In real-world practice, response rates and tolerability to brentuximab vedotin are similar to those reported in the two pivotal phase 2 trials in these settings.

[18F]fluorodeoxyglucose-positron emission tomography (PET) is emerging as a strong diagnostic and prognostic tool in follicular lymphoma (FL) patients.In a subset analysis of the FOLL05 trial (NCT00774826), we investigated the prognostic role of post-induction PET (PI-PET) scan. Patients were eligible to this study if they had a PI-PET scan carried out within 3 months from the end of induction immunochemotherapy. Progression-free survival (PFS) was the primary study end point.A total of 202 patients were eligible and analysed for this study. The median age was 55 years (range 33-75). Overall, PI-PET was defined as positive in 49 (24\%) patients. Conventional response assessment with CT scan was substantially modified by PET: 15\% (22/145) of patients considered as having a complete response (CR) after CT were considered as having partial response (PR) after PI-PET and 53\% (30/57) patients considered as having a PR after CT were considered as a CR after PI-PET. With a median follow-up of 34 months, the 3-year PFS was 66\% and 35\%, respectively, for patients with negative and positive PI-PET (P

No abstract available.

Purpose To assess the role of [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) after rituximab and anthracycline-containing chemoimmunotherapy in patients with primary mediastinal large B-cell lymphoma (PMLBCL). Patients and Methods Among 125 patients prospectively enrolled, 115 were eligible for central review of PET/CT scans at the completion of standard chemoimmunotherapy, by using a five-point scale. Consolidation radiotherapy (RT) was permitted and given to 102 patients. Results Fifty-four patients (47%) achieved a complete metabolic response (CMR), defined as a completely negative scan or with residual [18F]FDG activity below the mediastinal blood pool (MBP) uptake. In the remaining 61 patients (53%), the residual uptake was higher than MBP uptake but below the liver uptake in 27 (23%), slightly higher than the liver uptake in 24 (21%), and markedly higher in 10 (9%). CMR after chemoimmunotherapy predicted higher 5-year progression-free survival (PFS; 98% v 82%; P = .0044) and overall survival (OS; 100% v 91%; P = .0298). Patients with residual uptake higher than MBP uptake but below liver uptake had equally good outcomes without any recurrence. Using the liver uptake as cutoff for PET positivity (boundary of score, 3 to 4) discriminated most effectively between high or low risk of failure, with 5-year PFS of 99% versus 68% (P < .001) and 5-year OS of 100% versus 83% (P < .001). Conclusion More than 90% of patients are projected to be alive and progression-free at 5 years, despite a low CMR rate (47%) after chemoimmunotherapy. This study provides a basis for using PET/CT to define the role of RT in PMLBCL.

Peripheral T-cell lymphoma (PTCL) represents a relatively rare group of heterogeneous non-Hodgkin lymphomas with a very poor prognosis. Current therapies, based on historical regimens for aggressive B-cell lymphomas, have resulted in insufficient patient outcomes. The majority of patients relapse rapidly, and current 5-year overall survival rates are only 10-30%. It is evident that new approaches to treat patients with PTCL are required. In recent years, prospective studies in PTCL have been initiated, mainly in patients with relapsed/refractory disease. In some of these, selected histologic subtypes have been evaluated in detail. As a consequence, numerous new therapies have been developed and shown activity in PTCL, including: agents targeting the immune system (e.g. brentuximab vedotin, alemtuzumab, lenalidomide); histone deacetylase inhibitors (romidepsin, belinostat); antifolates (pralatrexate); fusion proteins (denileukin diftitox); nucleoside analogs (pentostatin, gemcitabine); and other agents (e.g. alisertib, plitidepsin, bendamustine, bortezomib). A variety of interesting novel combinations is also emerging. It is hoped that these innovative approaches, coupled with a greater understanding of the clinicopathologic features, pathogenesis, molecular biology, and natural history of PTCL will advance the field and improve outcomes in this challenging group of diseases. This review summarizes the currently available clinical evidence on the various approaches to treating relapsed/refractory PTCL, including the role of stem cell transplantation, with an emphasis on potential new drug therapies. peerReviewed

Background In order to promote widespread adoption of appropriate clinical practice, the Italian Society of Hematology (SIE), and the affiliate societies SIES (Italian Society of Experimental Hematology) and GITMO (Italian Group for Bone Marrow Transplantation) established to produce guidelines in the most relevant hematological areas. In this article, we report the recommendations for management of T/NK-cell lymphomas, excluding mature T-cell leukaemias. Design By using the Grades of Recommendations, Assessment, Development and Evaluation (GRADE) system, we produced evidence-based recommendations for the key clinical questions that needed to be addressed by a critical appraisal of evidence. The consensus methodology was applied to evidence-orphan issues. Results Six courses of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone (CHOEP) chemotherapy were recommended for first-line therapy of patients with nodal, intestinal or hepatosplenic T-cell lymphomas (evidence: low; recommendation: do, weak). Except for ALK+ anaplastic large-cell lymphoma and elderly unfit patients, consolidation with high-dose chemotherapy was recommended (evidence: low; recommendation: do, weak). 50 Gy radiotherapy was the recommended first-line therapy for localized extranodal T/NK-cell lymphoma nasal type (evidence: low; recommendation: do, strong), while l -asparaginase-containing chemotherapy regimens were recommended for patients with systemic disease (evidence: very low; recommendation: do, strong). Conclusion In adult T/NK-cell lymphomas, GRADE methodology was applicable to a limited number of key therapeutic issues. For the remaining key issues, due to lack of appraisable evidence, recommendations was based on consensus methodology.

Background Phosphatidylinositol-3-kinase delta (PI3Kδ) mediates B-cell receptor signaling and microenvironmental support signals that promote the growth and survival of malignant B lymphocytes. In a phase 1 study, idelalisib, an orally active selective PI3Kδ inhibitor, showed antitumor activity in patients with previously treated indolent non-Hodgkin’s lymphomas. Methods In this single-group, open-label, phase 2 study, 125 patients with indolent non-Hodgkin’s lymphomas who had not had a response to rituximab and an alkylating agent or had had a relapse within 6 months after receipt of those therapies were administered idelalisib, 150 mg twice daily, until the disease progressed or the patient withdrew from the study. The primary end point was the overall rate of response; secondary end points included the duration of response, progression-free survival, and safety. Results The median age of the patients was 64 years (range, 33 to 87); patients had received a median of four prior therapies (range, 2 to 12). Subtypes of indolent non-Hodgkin’s lymphoma included follicular lymphoma (72 patients), small lymphocytic lymphoma (28), marginal-zone lymphoma (15), and lymphoplasmacytic lymphoma with or without Waldenstrom’s macroglobulinemia (10). The response rate was 57% (71 of 125 patients), with 6% meeting the criteria for a complete response. The median time to a response was 1.9 months, the median duration of response was 12.5 months, and the median progression-free survival was 11 months. Similar response rates were observed across all subtypes of indolent non-Hodgkin’s lymphoma, though the numbers were small for some categories. The most common adverse events of grade 3 or higher were neutropenia (in 27% of the patients), elevations in aminotransferase levels (in 13%), diarrhea (in 13%), and pneumonia (in 7%). Conclusions In this single-group study, idelalisib showed antitumor activity with an acceptable safety profile in patients with indolent non-Hodgkin’s lymphoma who had received extensive prior treatment. (Funded by Gilead Sciences and others; ClinicalTrials.gov number, NCT01282424.)

Clinical trial results indicate that lenalidomide, an immunomodulatory drug, is a promising treatment in relapsed/refractory non-Hodgkin lymphoma (NHL). This retrospective multicenter study was conducted in patients with relapsed/refractory NHL treated with lenalidomide monotherapy through a Named Patient Program in Italy. Principal endpoints were overall response rate (ORR), safety and overall survival (OS). The ORR in 64 evaluable patients was 42.2\% and was similar among patients receiving 10, 15 or 25 mg/day lenalidomide. Response rates in patients with mantle cell, diffuse large B-cell and follicular lymphoma were 45.5\%, 42.1\% and 20\%, respectively. Among patients who responded to most recent prior therapy, ORR was 50.0\% versus 36.8\% in patients with refractory NHL. Mean duration of response in patients receiving any lenalidomide dose was 10.5 months; 1-year progression-free survival and OS were 50.3\% and 82.6\%, respectively. These findings suggest that lenalidomide is effective and safe for heavily pretreated patients with NHL in the clinical setting.

In a phase II trial, we evaluated chlorambucil and rituximab (CLB-R) as first-line induction treatment with or without R as maintenance for elderly chronic lymphocytic leukemia (CLL) patients. Treatment consisted of eight 28-day cycles of CLB (8 mg/m(2) /day, days 1-7) and R (day 1 of cycle 3, 375 mg/m(2) ; cycles 4-8, 500 mg/m(2) ). Responders were randomized to 12 8-week doses of R (375 mg/m(2) ) or observation. As per intention-to-treat analysis, 82.4\% (95\% CI, 74.25-90.46\%) of 85 patients achieved an overall response (OR), 16.5\% a complete response (CR), 2.4\% a CR with incomplete bone marrow recovery. The OR was similar across Binet stages (A 86.4\%, B 81.6\%, and C 78.6\%) and age categories (60-64 years, 92.3\%; 65-69, 85.2\%; 70-74, 75.0\%; ≥75, 81.0\%). CLB-R was well tolerated. After a median follow-up of 34.2 months, the median progression-free survival (PFS) was 34.7 months (95\% CI, 33.1-39.5). TP53 abnormalities, complex karyotype, and low CD20 gene expression predicted lack of response; SF3B1 mutation and BIRC3 disruption low CR rates. IGHV mutations significantly predicted PFS. R maintenance tended towards a better PFS than observation and was safe and most beneficial for patients in partial response and for unmutated IGHV cases. CLB-R represents a promising option for elderly CLL patients.