Primary Refractory Patients Research Articles

Outcome of Patients with Refractory Acute Leukemia Treated with a Third Induction Chemotherapy Regimen

Abstract 4305 BackgroundTreatment options are limited for refractory acute leukemia (AL) patients. Few data are available on the potential utility vs futility of a third course of induction chemotherapy. We have reviewed the characteristics and outcome of 35 patients treated with a third intensive induction course for refractory AL at our institution and other centers affiliated to the Quebec Leukemia Cell Bank (BCLQ). Methods and patientsAdult AL patients who never achieved complete remission (CR) or who relapsed within 6 months after 2 consecutive induction courses and who received a third line intensive induction course between 2000 and 2010 were included in this study. Clinical, laboratory and treatment data were collected from hospital and/or BCLQ files. Outcomes were measured after the third induction course. Primary outcomes were achievement of CR/CRi, overall survival (OS) at 12 months and event-free survival (EFS), defined as the percentage of patients alive and leukemia free at 12 months. Secondary outcomes included median OS, median duration of remission for those obtaining CR and treatment related mortality (TRM) associated with the third induction course. OS was estimated using the Kaplan-Meier method and survival curves were compared using the Log-rank test. Alive patients were censored at their last follow-up. ResultsThirty five patients met the inclusion criteria. The median age was 43 years old (20–62). Thirty one patients (89%) were diagnosed with AML and 4 patients (11%) with ALL or acute leukemia of ambiguous lineage. The median white blood cell count at diagnosis was 23 × 109/L (0.7–223). For AML patients, cytogenetics was favourable in 1 patient (3%), intermediate in 17 (55%) and adverse in 13 (42%). None of the 6 patients with normal karyotype for whom molecular characterisation was performed had a favourable genotype defined as NPM1 mutated without FLT3-ITD mutation. The patient with favourable karyotype had a variant t(8;21)(q22;q22) translocation without KIT mutation. Eighteen patients (51%) were primarily refractory to prior therapy and 17 (49%) had relapsed within 6 months of CR. The third line induction regimen consisted of cyclophosphamide and etoposide in 11 patients (31%), high dose cytarabine-based regimen in 10 (29%), mitoxantrone and etoposide in 7 (20%), fludarabine, cytarabine and idarubicin in 5 (14%) and other regimen in 2(6%). Patients with sustained remission after their third induction course were followed for a minimum of 12 months except for one patient alive and leukemia free at 6 months. Patients who were not in sustained remission have all been followed until death or transition to palliative care.CR after the third induction course was achieved in 6 patients (17%). At 12 months, OS was 11% and EFS was 6%. After the third induction, median OS was 5 months and median duration of remission was 6 months. Among 20 patients treated in our institution, the third induction TRM was 15% and median duration of hospitalisation, excluding patients who died in aplasia, was 38 days (20–70). Median OS was higher in the intermediate than in the adverse cytogenetics group (8 vs 2 mo, p=0.0008, figure 1) and in patients who achieved CR after third induction vs no CR (12 vs 4 mo, p=0.03). There was no difference in median OS between primary refractory and relapsed patients (8 vs 4 months, p=0.52).Allogeneic stem cell transplantation (SCT) was performed in 10 patients (29%) of whom 4 (40%) were in CR before transplantation. The only two long term survivors were in the allogeneic SCT group. Their percentages of blasts at transplant were 3 and 69 %. ConclusionOnly two refractory patients are long term survivors and they share several features: non adverse cytogenetics, young age (20 and 23) and they underwent allogeneic SCT. Adverse cytogenetics impinges negatively on outcome, even in this highly refractory group of subjects.The prognosis of AL patients with persistent disease after 2 induction courses is extremely poor and represents a major unmet therapeutic need. Refractory patients with adverse cytogenetics were unsalvageable in this series. The best approach for patients not in CR after 2 inductions probably remains allogeneic SCT, when possible. We consider that in patients who cannot be offered an allogeneic SCT, administration of a third course of conventional chemotherapy is practically useless. These patients should be considered candidates for investigational treatments. Disclosures:Bergeron: Merck: Research Funding; Roche: Honoraria; Celgene: Research Funding. [Display omitted]

Benefit from autologous stem cell transplantation in primary refractory myeloma? Different outcomes in progressive versus stable disease

Several studies of autologous stem cell transplantation in primary refractory myeloma have produced encouraging results. However, the outcome of primary refractory patients with stable disease has not been analyzed separately from the outcome of patients with progressive disease. In the Spanish Myeloma Group 2000 trial, 80 patients with primary refractory myeloma (49 with stable disease and 31 with progressive disease), i.e. who were refractory to initial chemotherapy, were scheduled for tandem transplants (double autologous transplant or a single autologous transplant followed by an allogeneic transplant). Patients with primary refractory disease included those who never achieved a minimal response (≥ 25% M-protein decrease) or better. Responses were assessed using the European Bone Marrow Transplant criteria. There were no significant differences in the rates of partial response or better between patients with stable or progressive disease. However, 38% of the patients with stable disease at the time of transplantation remained in a stable condition or achieved a minimal response after transplantation versus 7% in the group with progressive disease (P=0.0017) and the rate of early progression after transplantation was significantly higher among the group with progressive disease at the time of transplantation (22% versus 2%; P=0.0043). After a median follow-up of 6.6 years, the median survival after first transplant of the whole series was 2.3 years. Progression-free and overall survival from the first transplant were shorter in patients with progressive disease (0.6 versus 2.3 years, P=0.00004 and 1.1 versus 6 years, P=0.00002, respectively). Our results show that patients with progressive refractory myeloma do not benefit from autologous transplantation, while patients with stable disease have an outcome comparable to those with chemosensitive disease.

Chronic lymphocytic leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Chronic lymphocytic leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Positive HIV ELISA test, autoimmune hemolytic anemia, and generalized lymphadenopathy: A unifying diagnosis

Positive HIV ELISA test, autoimmune hemolytic anemia, and generalized lymphadenopathy: A unifying diagnosis

Primary anti-VEGF-refractory metastatic renal cell carcinoma (mRCC): Clinical characteristics, risk factors, and subsequent therapy.

305 Background: A proportion of patients treated with anti-VEGF therapy first line exhibit progressive disease (PD) as best response (per RECIST). The characteristics and outcome of this population are poorly understood. Methods: Data from patients with mRCC treated with anti-VEGF therapy were collected through the International mRCC Database Consortium from 12 centers. Results: One thousand fifty-six evaluable patients were treated with VEGF-inhibitors as their first-line antiangiogenic therapy. Of those, 272 (26%) patients had PD as best response. Their initial treatment was sunitinib (n=203), sorafenib (n=51), or bevacizumab (n=18). Six percent of patients were favorable risk, 55% intermediate risk, and 39% poor risk as per Heng et al JCO 2009 prognostic factors. On multivariable analysis, predictors of PD at first restaging were KPS < 80% (OR 2.3, p < 0.0001), diagnosis to treatment < 1 year (OR 2.1, p < 0.0001), neutrophilia (OR 1.9, p = 0.0021), thrombocytosis (OR 1.7, p = 0.0068), and anemia (OR 1.6, p = 0.0058). The median progression-free survival (PFS) and overall survival (OS) in patients with primary refractory disease vs. patients without (i.e., partial response or stable disease) was 2.4 vs. 11 months (p<0.0001) and 6.8 vs. 29 months (p<0.0001), respectively. Only 108 (40%) VEGF-refractory patients proceeded to receive 2nd line VEGF inhibitors (sunitinib (n=32), sorafenib (n=44), axitinib (n=2), bevacizumab (n=4)), mTOR inhibitors (temsirolimus (n=14), everolimus (n=11)), or interferon (n=1). The response rate, PFS and OS of this second-line therapy was 9%, 2.5 months and 7.4 months, respectively. The response rate, PFS and OS of those receiving second-line VEGF vs. mTOR inhibitors was 10% vs. 6% (p=NS), 2.8 vs. 2.0 months (p=0.069) and 7.9 vs. 4.7 months (p=0.40), respectively. Conclusions: Primary anti-VEGF-refractory mRCC patients have a dismal prognosis. Second-line anti-mTOR agents may not be better than alternate anti-VEGF agents after primary anti-VEGF failure. Investigation into the mechanism of primary resistance and alternative therapeutic strategies are needed. [Table: see text]

Did salvage ICE chemotherapy improve the outcome in primary resistant/relapsing stage III/IV neuroblastoma?

Background and purposeNeuroblastoma is the most common extracranial and deadly solid tumor in children. It accounts for 15% of the deaths from cancer in the pediatric age group. Approximately half of the newly diagnosed children are at “high risk” of treatment failure.The aim of this study is to evaluate the response rate of salvage chemotherapy by the ICE (Ifosfamide, Carboplatin, and Etoposide) regimen when administered to previously treated primary refractory or progressive high risk neuroblastoma patients. Patients and methodsSixty-six patients from the National Cancer Institute (NCI), Cairo University and the Children Cancer Hospital Egypt (CCHE) received salvage chemotherapy (ICE) either due to primary resistance in 51/66 (77.2%) or due to disease progression on primary chemotherapy in 15/66 (22.8%). ResultsThey were 40 males (60.6%) and 26 females (39.4%). Patients’ age ranged between 3months and 12.5years. The most common tumor site was suprarenal, followed by retroperitoneal mass. Two patients (3%) died from chemotherapy toxicity during ICE administration. Evaluation of tumor response in the remaining 64 patients showed the following: CR/PR in 24 patients (36.5%), SD in 11 patients (16.6%), and PD in 29 patients (43.9%).Fourteen patients (21.2%) were considered eligible for auto BMT, while 50/64 patients (78.8%) failed this second line (salvage) chemotherapy and had palliative lines of therapy.By the end of the study (May 2010), 47/66 (71.2%) of the patients were still alive, while 19/66 (28.8%) were dead. Two out of 14 patients (14.2%) who underwent HSCT died from post transplantation disease progression, while 12/14 (85.8%) were in CCR. ConclusionChemotherapy by ICE for primary resistant or progressive stage III/IV NB seems well tolerated. With a 36.6% response rate, 18% CCR, and 3% treatment mortality rate, it could be considered a good salvage therapy in the category of patients who are condemned for palliation.

Sorafenib Monotherapy Is Effective In Relapsed and RefractoryFlt3-ITD Positive Acute Myeloid Leukemia, Particularly After Allogenic Stem Cell Transplantation

AbstractAbstract 3314 Introduction:The FLT3-internal tandem duplication is the most frequent genetic aberration in normal karyotype acute myeloid leukemia (NK-AML) and associated with a poor prognosis. Patients with FLT3-ITD positive AML relapsing after allogenic stem cell transplantation (allo-SCT) have very limited therapeutic options. Sorafenib is a multikinase inhibitor, which is approved in Europe for the treatment of metastatic renal cell and hepatocellular carcinoma. It inhibits the FLT3 receptor tyrosine kinase, and, at low nanomolar concentrations also the mutated variant of FLT3, FLT3-ITD. Sorafenib also inhibits Raf, the platelet derived growth factor receptor (PDGFR) and the vascular endothelial growth factor receptor (VEGFR). We have previously reported that sorafenib monotherapy is effective in relapsed FLT3-ITD positive AML (Metzelder et al., Blood 2009; Metzelder et al., ASH 2009, poster #2060). Here we significantly extend these compassionate use experiences by reporting on clinical response details from 39 relapsed or refractory FLT3-ITD positive AML patients treated with sorafenib monotherapy. Methods:A questionnaire was developed and sent to 60 centers in Germany, Singapore and the United States, where FLT3-ITD-positive patients had been treated with sorafenib monotherapy. 26 centers returned information on therapy details of 55 patients. These included data on age, FAB-classification, karyotype, FLT3-ITD molecular testing, type and duration of response to prior therapy and to sorafenib, sorafenib dosing and tolerability. 16 patients were excluded from further analysis because of FLT3-ITD negativity or application of chemotherapy concomitant to sorafenib. Results:There were 39 evaluable patients (20 male, 19 female), grouped into i) primary refractory patients (PR-P) (n=11), receiving one (n=5) or two cycles (n=6) of chemotherapy before commencing sorafenib, ii) relapsing patients (REL-P) (n=12) with hematological recurrence after between one and four cycles of prior chemotherapy, syngenic, or autologous SCT, and iii) patients relapsing after allogenic SCT (SCT-P) (n=16). One patient was treated first line with sorafenib. One patient was treated before and after allo-SCT. Patients received between 200mg and 800mg sorafenib p.o. daily. The median treatment duration was 71 days (range, 13 to 270) for PR-P, 76 days (range, 9 to 160 days) for REL-P, and 76 days (range, 20 to 489 days) for SCT-P. All reported patients in this cohort responded to sorafenib. In the PR-P group, there were 6 hematological remissions (HR), characterized by complete (n=4) or near complete peripheral blast clearance (n=2), 4 complete remissions (bone marrow blasts < 5% with (CR) or without (CRp) normalization of peripheral blood counts) and one complete molecular remission (CMR, molecular negativity for FLT3-ITD). Six of these 11 PR-P underwent allo-SCT after responding to sorafenib induction. In the REL-P group there was one patient with a partial blast clearance (PR), 8 HR, 2 bone marrow responses (which includes a HR) and 1 CRp. In the SCT-P group there were 3PR, 2HR, 7 BMR and 4 CMR. Notably, the median time to treatment failure due to frank clinical sorafenib resistance was 119 days for PR-P and REL-P, but was not reached in the SCT-P group. This difference was statistically significant (p-value 0.0217). Sorafenib was generally well tolerated. Pancytopenia or thrombocytopenia grade III and IV were the most significant but manageable side effects. Other reported side effects such as diarrhea, exanthema were documented from the centers as being minor. Conclusion:This analysis on a large cohort of 39 FLT3-ITD positive patients confirms our previous reports on the remarkable clinical activity of sorafenib monotherapy in FLT3-ITD positive AML. Evidence is accumulating that sorafenib may be particularly effective in the context of allo-SCT, where long-term responses were seen. Disclosures:No relevant conflicts of interest to declare.

Macrophages and Mast Cells Infiltration Are Biomarkers of Primary Refractory Hodgkin's Lymphoma

AbstractAbstract 3881Classical Hodgkin's lymphoma is a highly curable lymphoma and about 80% of patients can be cured with modern treatment strategies. In spite of great clinical progress, a significant minority of classical Hodgkin's lymphoma experiences treatment failure after primary chemotherapy including a first line of anthracyclin-based regimen. Patients with refractory Hodgkin's lymphoma represent 5 to 10% of classical Hodgkin's Lymphoma. Many of these patients have a poor overall survival estimated at 25% at 5 years. A better biological characterization of such primary refractory patients might allow the use of early therapeutic intervention including targeted therapy. It remains, however, a challenge to identify patients whose disease will not be eradicated by standard therapy. Current prognostic models predict the outcome of treatment with imperfect accuracy, and clinically relevant biomarkers have not yet been established to improve the International Prognostic Score. For these reasons, reliable biomarkers for predicting long term survival at diagnosis are needed for such patients. Steidl et al. (Nejm,2010) recently reported the prognostic value of tumor-associated macrophages in patients with classical Hodgkin's lymphoma, showing that higher infiltration is associated with a shortened survival.The value of tumor-associated macrophages in primary refractory Hodgkin's lymphomas has not been specifically assessed. In a retrospective study (Canioni et al., Plos one 2009), we previously evaluated 59 patients (18 with primary refractory or early relapse disease and 41 responders) collected from 1997 to 2004 in two hematology centres (Necker Hospital and Gustave Roussy Institute, Paris France) for c-kit expression by immunohistochemical analysis as a marker of mast cell infiltration and correlated the results with the response to treatment. All available poor prognosis patients were first identified (18 patients with primary refractory disease or early relapse (< 1year)) and the control group (47 responders) was randomly selected. Patients received conventional chemotherapy-based treatments [(MOPP (mechlorethamine, vincristine, procarbazine, and prednisone), ABVD (doxorubicine, bleomycine, vinblastine, and dacarbazine) or the combination of both or BEACOPP (bleomycine, etoposide, doxorubicine, cyclophosphamide, vincristine, procarbazine, prednisone)] and radiotherapy in stages I and II. Most patients presented a nodular sclerosis subtype of Hodgkin's lymphoma regardless whether they were refractory (17/18cases, 94.5%) or responders (37/41cases, 90%). In this cohort, 44 (75%) patients had a localized stage, whereas 19 (25%) had a disseminated disease. The results showed that refractory Hodgkin's lymphoma were associated with an excess of mast cells infiltration in the tumor cells microenvironment. The number of mast cells stained was significantly higher in refractory Hodgkin's lymphoma (c-kit+ mast cells > 6 per field) than in responders (c-kit+ mast cells ≤ 6) (p=0.001 and 0.0194 in univariate and multivariate analysis, respectively). In this cohort of patients, using CD68 staining we also found a statistically significant higher proportion of tumor-associated macrophages in refractory Hodgkin's lymphoma as compared to responders in univariate and multivariate analyses (p=0.0048 and p=0.0041, respectively). Therefore, we confirmed a strong correlation between the number of CD68 positive macrophages in the tumor stroma and clinical outcome. The use of such markers (CD68 and c-kit) in combination with well-established clinical risk factors could improve on the predictive value of a single biomarker used alone.Therefore, in addition to mast cells, macrophages are also important players in refractory Hodgkin's lymphoma that may confer drug resistance to Hodgkin Reed Sternberg cells. Taken together, these data strongly suggest that microenvironment should be targeted in Hodgkin's lymphomas. In this regard, the use of kinase inhibitors that target both c-kit and M-CSF receptors could restore chemotherapy sensitivity in refractory Hodgkin's lymphoma and should be evaluated in clinical trials. Disclosures:No relevant conflicts of interest to declare.

An Effective Salvage Treatment Using Rituximab, Ifosfamide, Etoposide, Cytarabine, and Dexamethasone (R-IVAD) for Patients with Relapsed or Refractory Aggressive B-Cell Lymphoma

AbstractAbstract 1759 BackgroundThe prognosis of patients with relapsed or refractory aggressive B-cell lymphoma after the conventional first line chemotherapy is still disappointing. Although several rituximab combined salvage regimens were reported, the optimal treatment has not yet been established. We therefore evaluated the efficacy and toxicity of a non-anthracycline based salvage regimen, consisting of rituximab, ifosfamide, etoposide, cytarabine and dexamethasone (R-IVAD) in patients with relapsed or refractory aggressive B-cell lymphoma. Patients and methodsPatients with relapsed or refractory CD20-positive diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma grade 3 (FL G3) were consecutively enrolled in this treatment. R-IVAD consisted of rituximab (375 mg/m2 on day -2), ifosfamide (1500 mg/m2 on day 1–5), etoposide (150 mg/m2 on day 1–3), cytarabine (100 mg/m2 on day 1–3) and dexamethasone (40 mg/body on day 1–3). Treatment was given every 3 weeks up to a total of 3 courses with support of granulocyte colony stimulating factor. For responders under 65 years old with good performance status (PS), we planed peripheral stem cell collection after the third cycle of R-IVAD and consolidating high-dose chemotherapy (HDC) with cycrophosphamide (60 mg/kg on day -7,-6), etoposide (500 mg/m2 on day -6, -5, -4) and ranimustine (250 mg/m2 on day -3, -2) followed by autologous stem cell transplantation (ASCT). ResultsThirty-two patients (25 DLBCL and 7 FL G3) with a median age of 64 years old (range 38–79) participated in this study and received an average of 2.6 cycles of R-IVAD. There were 21 relapsed and 11 primary refractory patients. The overall response (OR) and the complete response (CR) rate were 72% and 56% respectively. The OR rate of relapsed patients was significantly higher than that of primary refractory patients (86% vs. 45%, p=0.035). With a median 16 months (range 2–99) of follow up, the 2-year overall survival (OS) and the event-free survival (EFS) for all patients were 55% and 36% respectively. Of the 11 eligible patients, 10 successfully proceeded to HDC/ASCT with an average of 5.5 × 106/kg of harvested CD34-positive cells, resulting in the 2-year OS of 90%. No treatment related death was observed during the investigation. Multivariate analysis revealed that the age > 60 years, PS ≥ 2, extranodal sites ≥ 2, and primary refractory disease were independently associated with worse survival. ConclusionR-IVAD regimen, which efficiently mobilizes peripheral stem cells, is a safe and efficacious alternative for patients with relapsed or refractory aggressive B-cell lymphoma. Disclosures:No relevant conflicts of interest to declare.

Gemcitabine and vinorelbine combination is effective in both as a salvage and mobilization regimen in relapsed or refractory Hodgkin lymphoma prior to ASCT

We investigated the efficacy of gemcitabine and vinorelbine (Gem/Vin) combination chemotherapy as a salvage and mobilization regimen in relapsed or refractory Hodgkin lymphoma (HL) patients prior to autologous hematopoietic stem cell transplantation. We retrospectively reviewed the data of our relapsed or primary refractory HL patients treated with Gem/Vin regimen which consisted of gemcitabine 1,000mg/m(2)/day and vinorelbine 30mg/m(2)/day on days1, 8, and 15 every 28days. The overall response rate was 72.4%. Ten (34.5%) patients achieved complete remission, 11 (37.9%) partial remission, and eight (27.6%) patients had no response. Mobilization with Gem/Vin regimen was successful in 20/23 (87%) patients while mobilization failure was seen in three (13%) patients. Gemcitabine and vinorelbine is an effective salvage regimen with acceptable toxicity and high mobilization potential in relapsed or refractory HL patients.

Outcome of pediatric patients with Langerhans cell histiocytosis treated with 2 chlorodeoxyadenosine: a nationwide survey in Japan

The aim of this study was to assess the outcome of treatment with 2-chlorodeoxyadenosine (2-CdA) in pediatric patients with Langerhans cell histiocytosis (LCH) in Japan. We retrospectively identified 17 pediatric LCH patients treated with 2-CdA. All patients were refractory or reactivated cases who had been initially treated according to the JLSG-02 protocol of the Japan LCH study group. At initiation of 2-CdA therapy, 4 patients had primary refractory multisystem (MS) disease with risk organ (RO) involvement (MS+), 9 patients had reactivated MS disease [5 MS+ and 4 without RO involvement (MS-)], and the remaining 4 patients had refractory/reactivated multifocal bone disease (MFB). Treatment with 2-CdA (4-9 mg/m(2)/day) was administered on 2-5 consecutive days and repeated every 3-4 weeks for a period that ranged from 2 to 12 months. Four primary refractory patients were treated with 2-CdA combined with high dose of cytarabine. In MS+ patients, response to treatment was observed in 5 of the 9 patients. In MS-/MFB patients, 5 of the 8 patients showed response to treatment. In the patients who were primary refractory or had reactivation during initial chemotherapy, 4 of 10 patients showed good response. On the other hand, in the patients having reactivation while off therapy, 6 of 7 patients showed good response. These findings suggest that 2-CdA is effective for reactivated LCH while off therapy.

Donor Lymphocyte Infusions Induce High Response Rates and Durable Salvage in Relapsed Hodgkin Lymphoma Post T Cell Depleted Allogeneic Transplantation.

Abstract 200The feasibility of performing allogeneic HSCT in patients with Hodgkin Lymphoma using reduced intensity conditioning (RIC) is well established. By reducing non-relapse mortality, these approaches have seemingly improved post-transplant survival outcomes compared to conventional myeloablative strategies. An EBMT registry analysis comparing outcomes with fully ablative protocols confirmed an overall survival advantage for RIC in adult patients (Sureda et al, JCO, 2008). Relapse rates, however, were higher following RIC, and relapse now represents the major cause for treatment failure following allogeneic transplant in HL. Identifying strategies that reduce relapse rates or more effectively salvage relapsing patients is therefore an imperative. There is no consensus regarding these issues, and little published evidence to guide practice. We have performed 72 RIC allografts for HL (38 matched sibling, 34 unrelated donor) incorporating T cell depletion with alemtuzumab at our institution. This high risk cohort included 33 primary refractory or salvage-refractory patients, and 53 had failed a prior autograft. Patients were monitored for lineage-specific chimerism using a PCR-based STR assay, and disease status assessed by CT-PET, potentially allowing earlier intervention for relapse. Patients received a dose-escalating donor lymphocyte protocol from 6 months post transplant for mixed chimerism or residual disease/progression. Relapse was defined by recurrence or progression of FDG-avid lesions in sites of prior disease, with or without new sites. In cases where FDG-avid lesions occurred only in new sites relapse was confirmed by biopsy if accessible (n=3), otherwise an interval scan was performed at 6–8 weeks to confirm progression in the absence of other potential pathology. Cyclosporine was withdrawn prior to consideration of DLI, which was not given to patients with active GvHD. Non-relapse mortality was 13% at 1 year and 15% at 3 years post transplant. Cumulative incidence of relapse was 46% at 3 years. Forty patients have received a total of 78 DLIs (median 2 doses, range 1–5). Median CD3+ T cell dose was 3×10e7/kg (range 1×10e6–3×10e8/kg). Treatment was given for mixed chimerism alone in 19 patients, with up to 90% recipient chimerism. This group included 9 who were primary refractory or salvage refractory prior to transplant. DLI resulted in conversion to full donor status in 12/15 evaluable patients, 2 continue to show falling recipient chimerism, and 1 failed to convert. Three are currently too early to assess and 1 died prior to evaluation. Nine remain free from GvHD, suggesting that conversion can occur in its absence. Only 1 patient in this cohort subsequently relapsed (cumulative incidence 7% at 3 years from initial DLI), and this occurred in the setting of persistent mixed chimerism. The patient received further DLI following cytoreductive chemotherapy. Disease relapse was treated in 22 patients with DLI either alone (n=15) or following debulking chemo-radiotherapy (n=7). Five relapsed/progressive patients did not receive DLI, either because of early progression within 3 months of transplant, concurrent GvHD, or lack of donor availability. Median starting doses of DLI were 1×10e6 and 1×10e7 CD3+ T cells/kg in unrelated and related donors respectively, and median maximal doses 3×10e6 and 3×10e7/kg respectively. Complete responses were seen in 10 (50%) and partial responses in 5; overall response 75% of 20 evaluable patients. The majority of responders (9/10 CR, 4/5 PR) developed GvHD (5 acute grade III–IV, 4 extensive chronic). CR is maintained in 6 patients at a median of 4.8 years (range 1.3–7.5 years) from last DLI (5/6 received DLI alone at relapse, and 4 have no current GvHD), 3 died in CR of complications of GvHD, and only 1 progressed (at 2.3 years). 2/5 with PR progressed, and follow-up in the others is short (<12 months). With a median follow-up of 2.5 years from relapse the projected 3 year OS and PFS from time of relapse are 62% and 52% in this cohort of 22 patients. The OS and current PFS for the entire cohort (n=72) are both 45% at 6 years. In conclusion, the data demonstrate favorable long term survival in this heavily pre-treated cohort, a strikingly low relapse incidence in those receiving DLI for mixed chimerism, and the ability of DLI guided by CT-PET restaging to induce high response rates and durable salvage in the setting of relapse post T cell depleted transplantation in HL. Disclosures:No relevant conflicts of interest to declare.

RIC Allogeneic Transplantation Improves the Overall and Progression- Free Survival of Hodgkin Lymphoma Patients Relapsing after Autologous Transplantation: A GITMO Retrospective Study Based on Time of HLATyping and Donor Availability

Background: Hodgkin Lymphoma (HL) patients (pts) relapsing after autologous transplantation (auto-SCT) have a very poor outcome with no chemotherapy options able to obtain a long term disease control. Allogeneic stem cell transplantation (allo-SCT) employing reduced intensity conditioning (RIC) is increasingly used in lymphomas, but the number of studies in HL is quite limited, some groups reported conflicting results, and thus no clear evidence exists on its role as an effective salvage option in the clinical setting.Aims: We investigated the role of RIC allo-SCT in HL pts relapsing or progressing after auto-SCT (primary refractory patients were not included). Our study was structured similarly to an intent to treat analysis, and thus was based on the commitment of the attending physician to perform an allo-SCT. Only those pts undergoing a HLA-typing immediately after the failure of auto-SCT were included. The cohort of pts having a donor (donor group) was compared with the one not having a suitable donor (no donor group).Patients and Methods: 132 pts were retrospectively evaluated, for all of them a search for a sibling or matched unrelated donor (MUD) was started at the time of relapse/progression after auto-SCT. Seventy-five pts found a donor and 68 (90%) underwent an allo-SCT: 36 identical siblings (52%), 23 MUD (33%), 6 haploidentical family donors (9%). Thiotepa, cyclophosphamide and fludarabine containing regimens were used in all pts; GVHD prophylaxis was based on MTX and cyclosporine except for haploidentical-SCT. Seven pts having a donor did not receive allo-SCT for progressive disease. Pts not having a donor (n= 57) received chemo- and/or radiotherapy according to the standard policy of each center. The two cohorts of patients were well balanced in terms of clinical features, in particular the number of patients relapsing/progressing within 6 months from auto-SCT was similar.Results: The patient median age was 30 years (17–62). The median followup was 24 months. For all pts, the median overall (OS) and progression free survival (PFS) were 31 and 15 months, respectively. The 2-year OS and PFS were 56% and 29% respectively. The cumulative transplant-related mortality was 12% for the donor group. The 2-y OS and PFS were significantly better in the donor compared to the no donor group (OS 70% vs 38.8%, p 0.001, long rank test; PFS 42% vs 10%, p 0.03, long rank test). In multivariate analysis having a donor was statistically significant for OS and PFS. When we considered only the pts actually allografted, again the 2-years OS and PFS were significantly better compared to the no allo-group (OS 77% vs 35% and PFS 47% vs 9.3%). Acute GVHD grade II-IV occured in 17 pts (25)% and chronic GVHD in 27 pts ( 40%). In multivariate analysis, being in complete remission before allo-SCT significantly improved OS and PFS.Conclusions: This is the largest study comparing RIC allo-SCT vs conventional treatment in HL patients failing an auto-SCT. Allo-SCT is a feasible option and prolongs OS and PFS. As expected, the attainment of complete remission before allo-SCT improves the outcome.

Sequential continuous infusion of fludarabine and cytarabine associated with liposomal daunorubicin (DaunoXome®) (FLAD) in primary refractory or relapsed adult acute myeloid leukemia patients

A large proportion of adult patients with acute myeloid leukemia (AML) relapse after treatment, and some of them are resistant to primary induction chemotherapy. Sixty-one patients from seven hematological centers with poor-risk AML, primary refractory (n = 16), or relapsed (n = 45) were treated with a salvage regimen, including fludarabine (2 days) and cytarabine (3 days) in a sequential continuous infusion, associated with liposomal daunorubicin (3 days) (FLAD). Complete response rate was 44% and 56% for refractory and relapsed patients, respectively, with an overall response rate of 52% (32 of 61). Twenty-two patients (36%) were resistant to the salvage therapy. Seven patients (12%) died early during chemotherapy, four of them because of sepsis. Nineteen patients in complete remission (CR) underwent a stem-cell transplant (SCT) procedure: five autologous, nine from a HL-A identical sibling, and five from HL-A matched unrelated donors. Post-treatment aplasia and mucositis were major toxicities. Twenty patients (62.5%) relapsed after this treatment in a median of 7.3 months; ten patients relapsed after a SCT procedure. Nine patients are alive and disease free; three of them were rescued after a further cytotoxic treatment. The FLAD regimen proved to be an effective and well-tolerated treatment, with acceptable toxicity in this group of high-risk patients. A better response rate was obtained in the subgroup of relapsed patients, compared to patients treated for refractory disease. More then half (five of nine) of long-surviving patients are those who were submitted to a transplant procedure; thus, the main indication for FLAD seems to be to try to induce a rapid CR with minimum toxicity in order to perform a transplant as soon as possible.

Equitoxicity of bolus and infusional etoposide: results of a multicenter randomised trial of the German High-Grade Non-Hodgkins Lymphoma Study Group (DSHNHL) in elderly patients with refractory or relapsing aggressive non-Hodgkin lymphoma using the CEMP regimen (cisplatinum, etoposide, mitoxantrone and prednisone)

To compare toxicity of etoposide bolus with continuous infusion and to assess the efficacy of the CEMP (cisplatinum, etoposide, mitoxantrone, prednisone) regimen, 47 patients with refractory or relapsed aggressive non-Hodgkin's lymphoma older than 60 years (n=43) or not qualifying for high-dose chemotherapy (n=4) received five four-weekly CEMP cycles. Patients were randomised to start with bolus or continuous-infusion etoposide and then received bolus and infusional etoposide in an alternating fashion. The primary objective was the comparison of differences in the course of leukocytopenia and thrombocytopenia between the two application schedules. CEMP was well tolerated with little organ and moderate haematotoxicity. There was no difference in toxicity between bolus and continuous-infusion etoposide. Complete remission rate was 44% in patients relapsing >or=1 year, 27% in patients relapsing within the first year after achieving complete remission and 5% in primary refractory patients. Median event-free and overall survivals for all patients were 3 and 10 months, respectively. The observed equitoxicity and the more challenging logistics of a 60-h infusion make bolus injection the preferred application of etoposide. As the CEMP regimen is well tolerated and efficacious in elderly patients with relapsed or refractory aggressive non-Hodgkin's lymphoma for whom more aggressive therapies are not feasible, a three-weekly modification of CEMP should be tested in combination with rituximab.

Phase II study of sequential topoisomerase (Top) targeting regimens (reg) with irinotecan/oxaliplatin (I/O) followed by etoposide/carboplatin (E/Crb) in patients with extensive small cell lung cancer (SCLC)

19095 Background: Top inhibitors are active agents in SCLC, and preclinical models indicate that sequential administration of Top I and Top II targeting drugs can result in additive or synergistic antitumor activity. Methods: The primary objective of this study is to determine the objective response (OR) rate of sequential I/O (Regimen A) followed by E/Crb (Regimen B). Secondary endpoints include toxicities (Tx), time to progression (TTP), overall survival (OS), and immunohistochemical (IHC) evaluation of Top I/II and excision repair cross complementation I (ERCC-I) expression in tumor specimens. Chemotherapy naïve patients receive 5 cycles of sequential therapy of reg A→B. Each cycle consists of I (150–200 mg/m2) and O (85mg/m2) on day 1 followed by Crb (AUC = 6) on day 15 and E (100mg /m2) on days 15, 16, and 17. Pegfilgastrim (6mg) is given on days 2 and 18 of each 28 day cycle. Response assessment is performed after every 2 cycles. Primary refractory or relapsed patients are treated with reg A only. Results: Demographic characteristics of the 26 enrolled patients are: median age 62; gender ratio 13/13 (male/female); 10 with performance status 0–1; and 3 have primary refractory disease upon enrollment. Four patients are not included in the response data, 3 are too early to evaluate and 1 was evaluable for Tx only. Data from chemotherapy naïve patients with > 2 cycles of treatment (n=16) indicate 1 complete response, 13 partial responses, and 2 with stable disease. The median TTP is 7.5 months in the 6 patients with progression. No OR are observed in previously refractory patients (n=3). Grade 3 and 4 Tx in the 1st cycle of regimen A are neutropenia (ANC) (n=3) and fatigue (n=13). Reg B Tx are anemia (HGB) (n=5), ANC (n=5), thrombocytopenia (PLT) (n=16), and fatigue (n=4). The most common overall Tx in reg A are mild to moderate nausea and vomiting and HGB. The main dose limiting Tx (DLT) is grade 4 PLT in reg B. Conclusions: Early data indicates that this sequential approach may enhance the efficacy of chemotherapy in newly diagnosed SCLC patients. This study is actively enrolling patients, and updated findings including efficacy and pharmacogenomic correlations will be presented. No significant financial relationships to disclose.

A multicenter study of gemcitabine-containing regimen in relapsed or refractory Hodgkin's lymphoma patients

The aim of this study was to assess the efficacy of a gemcitabine-containing regimen in pretreated Hodgkin's lymphoma (HL) patients. Relapsed or refractory HL patients treated with gemcitabine, used alone or in combination with other cytotoxic agents, were retrospectively reviewed. Fifty-five patients were included in the study. Initial characteristics before gemcitabine administration were: Ann Arbor stage III-IV: 84%; International Prognostic Score less than 3 in 18/39 cases (46%); 31 primary refractory patients at the end of first-line therapy (56%); median number of previous chemotherapy regimens of 3. Twenty-nine patients received gemcitabine alone with a median maximal dose of 900 mg/m2 per injection (range: 300-1500 mg/m2). Gemcitabine was administered at a maximal dose of 1000 mg/m2 per injection (range: 650-1250) in combination with vinorelbine in 10 patients, oxaliplatin in 13 patients, and other drugs in three patients, with a median of six injections (range: 1-18). Reported toxicity was mainly hematologic. Overall response rate was 20% with 11% of complete remission. On univariate analysis, two adverse factors at progression were significant for response to gemcitabine-based regimen: stage III-IV disease and hemoglobin level was less than 10.5 g/dl. This study demonstrated the limited efficacy of gemcitabine-containing regimen in heavily pretreated HL patients.

Managing relapsed and refractory Hodgkin lymphoma

Despite a high curability rate, some patients with Hodgkin lymphoma (HL) fail to respond to, or relapse after, primary conventional treatment. This review aims to identify prognostic factors at relapse and guidelines for treatment in relapsed HL. Patients with relapsed HL should be identified according to their prognostic factors at relapse (duration of remission and extranodal disease or stage). This enables relapsing patients to be separated in to three different prognostic groups; primary refractory patients should be included in the unfavourable group because of their poor prognosis. All relapsed HL should receive second-line chemotherapy and the response to this chemotherapy is crucial for the outcome. Benefit of autologous stem-cell transplantation (ASCT) has been shown in a large randomized study and, although is often proposed in relapsed HL, it may be not necessary in the rare group of patients with stage I/II and late relapse who can receive additional radiotherapy after response to chemotherapy. Patients with intermediate and unfavourable relapse should receive high-dose chemotherapy and ASCT when chemosensitive; the first goal is to achieve this chemosensitivity. For patients in the unfavourable group, including refractory patients, the role of tandem HDT or allogeneic SCT will be discussed and should be proposed for patients not in complete remission at the time of HDT.

A Multicenter Study of a Gemcitabine-Based Regimen in Relapsed or Refractory Hodgkin's Lymphoma Patients.

The aim of this study was to assess the efficacy of a gemcitabine-based regimen in pretreated Hodgkin's lymphoma (HL) patients. Relapsed or refractory HL patients treated with gemcitabine, used alone or in combination with other cytotoxic agents, were retrospectively reviewed. Fifty-five patients were included in the study. Initial characteristics before gemcitabine administration were: Ann Arbor stage III–IV: 84%; International Prognostic Score less than 3 in 20/43 cases (47%); thirty-one primary refractory patients at the end of first-line therapy (56%); median number of previous chemotherapy regimens of 3. Twenty-nine patients received gemcitabine alone with a median starting dose of 750 mg/m2 per injection (range: 180–1250 mg/m2); Gemcitabine was administered at a starting dose of 1000 mg/m2 per injection (range: 500–1250) in combination with vinorelbine in 10 patients, oxaliplatin in 13 patients, and other drugs in 3 patients, with a median of 6 injections (range: 1–18). Overall response rate was 20% with 11% of complete remission. On univariate analysis, two adverse factors at progression were significant for response to gemcitabine-based regimen: stage III–IV disease and hemoglobin level less than 10.5 g/dl. In conclusion, the two identified prognostic factors for response to gemcitabine are part of the International Prognostic Score of HL, suggesting that response to gemcitabine is mainly influenced by the specific prognostic factors of HL. Moreover, with an ORR of 29%, our results of the gemcitabine administered alone regimen are not different from those reported in the literature. In contrast, the results of the various series of HL patients treated by gemcitabine-combined regimens, mainly with cisplatin or derivatives, vinorelbine, ifosfamide, doxorubicin, and prednisone, are very different due to different patient characteristics. In heavily pretreated cases, as in our study, the ORR was 26%; inversely, in patients who had received only one or two lines of chemotherapy, the ORR varied between 64% and 82% with 9% to 54% of complete remissions. This discordance can probably be explained by the prognostic impact of previous treatment lines in the response to gemcitabine. This observation emphasizes the possible interest of using gemcitabine earlier in the treatment of Hodgkin's lymphoma, namely at the time of first relapse or after first-line treatment in primary refractory HL patients.

Relapsed and Primary Refractory Diffuse Large B-Cell Lymphoma: Improving Outcome by Incorporating Involved Field Radiotherapy into a Comprehensive Second-Line High-Dose Therapy Strategy.

Primary refractory or relapse patients (pts) who have not achieved complete response after salvage or re-induction therapy carry poor prognosis even if additional high-dose chemotherapy is given. In a cohort of 171 pts with relapsed or refractory DLBCL, treated at MSKCC between 1/1/1994 to 9/1/2006 with ICE (ifosfamide, carboplatin, etoposide)-based salvage chemotherapy (44% received ICE+ Rituximab) followed by high dose chemotherapy with autologous stem cell rescue (HDT/ASCR), all pts had post-ICE functional imaging (FI) (Gallium or PET scan). All pts were required to have improvement on CT scan after ICE to be eligible for HDT/ASCR. Involved field radiotherapy (IFRT) was given (prior to HDT/ASCR) to sites of previously unirradiated bulky disease (>5 cm) or to sites with residual nodal masses of more than 2 cm in size following ICE. IFRT was administered within two weeks in 1.5 Gy fractions twice daily to a total dose of 30 Gy if given alone, or to a dose of 18 Gy if given in combination with 12 Gy fractionated total body irradiation. At a median follow-up of 57 months for surviving pts, there were no treatment-related deaths, and the 5-year progression-free survival (PFS) and overall survival (OS) for the entire cohort was 51% and 57%, respectively. Following ICE-based cytoreduction, FI was positive in 65 pts (38%) and they had an inferior 5 yr PFS (30% vs 61%, p=0.001) and OS (37% vs 67%, p<0.001) compared to those with a negative test. In the pts with positive FI scan, IFRT was delivered to all positive sites based on FI in 40 pts, while 25 pts had incomplete or no IFRT coverage to the positive sites. Eleven pts could not receive further IFRT, due to a history of prior IFRT as part of initial front-line treatment. In pts with positive FI, complete IFRT coverage had an improved 5yr-PFS (44% vs 19%; p=0.05). In a Cox regression multivariate analysis of the pts with positive FI, two factors remained independently significant for inferior PFS: 1. higher age-adjusted second-line IPI scores, and 2. no IFRT, or inadequate IFRT (incomplete coverage of all positive areas). Adequate radiation reduced the risk of progression/relapse by approximately 50%.Conclusion: Patients with positive FI following ICE have a worse PFS compared with pts with negative FI to ICE. Higher adjusted IPI scores are associated with even worse outcomes in this group of pts. If all sites of abnormal FI post-ICE can receive IFRT prior to HDT/ASCR, PFS is likely to improve.Multivariate AnalysisPatientsHR95% CIP valueIFRT: incomplete coverage251.00referenceIFRT: complete coverage400.510.26, 1.020.057sAAIPI: 0111.00referencesAAIPI: 1223.981.13, 13.980.031sAAIPI: 2&3243.421.00, 11.790.051Abbreviations: HR-Hazard Ratio; CI-Confidence Interval; sAAIPI-age-adjusted second-line IPI score