Unmaintained Remission Research Articles

Interruption of imatinib in advanced gastrointestinal stromal tumor after prolonged imatinib maintenance in the absence of gross tumor lesions.

Current guidelines recommend indefinite imatinib treatment for advanced gastrointestinal stromal tumor (GIST) patients. Imatinib-refractory progression-free survival (PFS) and overall survival were previously reported not to differ between GIST patients who interrupted imatinib and those who did not. Clinical outcomes of 77 consecutive patients with recurrent or metastatic GIST who interrupted imatinib treatment after maintaining years of imatinib treatment in the absence of gross tumor lesions were retrospectively analyzed. Associations between clinical factors and progression-free survival (PFS) following imatinib interruption were analyzed. The median time from the absence of gross tumor lesions to imatinib interruption was 61.5months. Since imatinib interruption, the median PFS was 19.6months, and 4 patients (26.3%) remained progression-free for longer than 5years. Among the patients who had progressive disease following the interruption, imatinib re-introduction led to an 88.6% objective response rate and a 100% disease control rate. Complete removal of the initial gross tumor lesion(s) and complete removal of the residual gross tumor lesion(s) by local treatment (vs. no local treatment or residual lesions after local treatment) were independently associated with favorable PFS. Interruption of imatinib following prolonged maintenance in the absence of gross tumor lesions led to disease progression in the majority of cases. However, re-introduction of imatinib resulted in effective tumor control. Unmaintained remission seems to be possible in some patients with metastatic or recurrent GIST after a prolonged remission with imatinib if there is complete removal of any gross tumor lesions.

Cautious addition of targeted therapy to PD-1 inhibitors after initial progression of BRAF mutant metastatic melanoma on checkpoint inhibitor therapy

BackgroundVirtually all metastatic patients with metastatic melanoma who progress after initial treatment with PD-1 or CTLA-4 directed antibodies will die of their disease. Salvage options are urgently needed. It is theoretically attractive to combine immunotherapy with targeted agents in progressing patients with BRAF mutation positive melanoma, but the toxicity of combined treatment has proven challenging.MethodsWe performed a retrospective analysis of our patient database and identified 23 patients who progressed on initial checkpoint inhibitor treatment, who subsequently had cautious addition of BRAF±MEK inhibitor therapy to continued PD-1 antibody treatment.ResultsWe found an objective response rate of 55% in second line therapy, with a median progression-free survival of 33.4 months and median overall survival of 34.1 months, with 40% of patients in unmaintained remission at over 3 years. Ten of 12 responding patients were able to discontinue all therapy and continue in unmaintained remission. Toxicity of this approach was generally manageable (21.7% grade 3–5 toxicity). There was 1 early sudden death for unknown reasons in a responding patient.DiscussionOur results suggest that 2nd line therapy with PD-1 inhibitors plus BRAF±MEK inhibitors has substantial activity and manageable toxicity. This treatment can induce additional durable complete responses in patients who have progressed on initial immunotherapy. These results suggest further evaluation be performed of sequential PD-1 antibody treatment with cautious addition of targeted therapy in appropriate patients.

Unusual Long Term Remission in Multiple Myeloma Using Conventional Therapy Combined with Danazol

Introduction and Case studies. The treatment of multiple myeloma (MM) has drastically changed over the past decade with significantly improved progression free as well as overall survival. Despite the advent of multiple treatment options, MM still has the inherent ability to become resistant. Relapses are frequent and the disease becomes refractory to treatment, leading to significant morbidity and mortality. Long term remissions lasting over a decade without relapses are rare in MM with conventional treatment.We report here prolonged remission lasting for decades in two patients with MM who were treated with conventional alkylating agents and steroids, combined with danazol as adjuvant and maintenance therapy. Both achieved complete remissions with undetectable M proteins and remarkable clinical improvement and better quality of life. The remissions were maintained now over two decades.Our first case was a 51 year old man who presented with severe back pain and noticeable loss of height. Work up revealed many lytic lesions and multiple collapsed vertebrae with diffuse osteoporosis on skeletal bone survey. Hematologic studies revealed high levels of IgG-lambda M protein of 6 grams. He was treated with melphalan, prednisone, monthly Aredia and danazol 200 mg three times daily (TID). He achieved a complete remission (CR) with marked clinical improvement. His remission was maintained with danazol 200 mg TID and Intron-A (interferon alfa-2b, recombinant) 5 million units three times a week. Danazol was later reduced to three times a week in combination with interferon, doses of which he remains on today. He remains in CR now for over 21 years without signs of relapse. He resumed all of his normal activities and is currently working without any limitation as a full time college professor. He refuses to stop danazol nor Intron-A.Our second case was a 41 year old man with 3 year history of progressive polyneuropathy that rendered him severely paraplegic, bedridden and unable to feed himself because of weakness. Work up revealed an IgG lambda M protein and multiple sclerotic bone lesions on bone survey. Excisional bone biopsy showed neoplastic plasma cell proliferation. Diagnosis of osteosclerotic multiple myeloma with POEMS syndrome was made. He was treated initially with plasmapheresis and infusions of IVIG without any long tern benefit. Subsequently, he received palliative radiation therapy to relieve bone pain and was treated with chlorambucil 3 mg PO daily, hydrocortisone 20 mg PO daily, danazol 200 mg PO TID and monthly Aredia which was later changed to Zometa. He achieved a CR with remarkable clinical recovery. His strength improved significantly with the ability to walk and feed himself as well as resumption of his normal daily activities (Muscle Nerve. 1997, 8:1035). He stopped danazol and remains in remission now over 22 years.Conclusion/Discussion: The use of immunomodulators (IMiDs) have changed the approach to the treatment of MM. While the mechanism of action is not fully understood, IMiDs appear to possess anti-myeloma properties including immunomodulation, anti-angiogenesis, and anti-proliferative activities (Leukemia. 2010, 24:22).Danazol, an attenuated androgen, is widely used in the treatment of ITP (NEJM. 1983, 308:1396). We previously showed that danazol carries inherent immunomodulatory action, increasing T-helper cells as well as the proportion of T-helper to T-suppressor cells among patients treated for ITP (Clin Imm Immunopath. 1987, 42:287). Administration of danazol in patients for ITP for over a year, even with withdrawal, yielded long term remissions while relapses were more frequent in those that took it for less than 6 months (Ann Intern Med. 1989, 111:723). Similar observation was made in other autoimmune disease such as immune hemolytic anemia (Acta Hematol. 1990, 84:122). Collectively, long term administration of danazol appears to induce prolonged unmaintained remission in autoimmune diseases like ITP. We postulate that danazol may induce similar immunomodulation in MM and contributed to decades of remission in our patients. Danazol has not yet been tested in the treatment of MM systematically but deserves further investigation through a large prospective clinical trial. DisclosuresNo relevant conflicts of interest to declare.

Treatment of Poor Risk Acute Leukemia With Sequential High-Dose ARA-C and Asparaginase

Resistance of leukemia cells to cytosine arabinoside (ARA-C) may be due to any one or combination of biochemical processes, which in certain instances may be substantially reversed by an appropriate increase in ARA-C dosage. Based on these and other laboratory observations indicating pharmacologic synergy between sequential high-dose ARA-C and asparaginase (HiDAC----ASNase), a therapeutic program was developed for the treatment of patients with acute nonlymphocytic leukemia (ANLL) refractory to conventional doses of ARA-C, as well as patients with high risk ANLL and advanced acute lymphocytic leukemia (ALL). Treatment consisted of 3-hr intravenous infusions of 3 g/sq m of ARA-C given at 12-hr intervals for 4 doses, followed by 6,000 IU/sq m ASNase given i.m. at hour 42. The same schedule was repeated on day 8. In 32 induction attempts, only 4 patients proved to be truly refractory, i.e., failed to achieve substantial leukemia cell cytoreduction. Complete remissions were achieved with HiDAC---- ASNase in 9 of 13 patients with refractory ANLL, 6 of 9 patients with antecedent hematologic disorders, and 3 of 10 patients with advanced ALL. These include 9 of 14 patients who had either failed induction or who had relapsed on active ARA-C therapy and 6 of 8 patients who had had no prior exposure to ARA-C. The median duration of unmaintained remission in ANLL was 5 mo. In a patient with central nervous system (CNS) leukemia, there was clearance of cerebral spinal fluid (CSF) blasts without intrathecal therapy, suggesting a role for HiDAC in CNS prophylaxis. In general, toxicity was tolerable and reversible. These data suggest that HiDAC----ASNase is an exceptionally effective and well tolerated regimen in leukemic patients with antecedent hematologic disorders and in those refractory to conventional doses of ARA-C.

Intensive Combination Chemotherapy and X-Irradiation in Hodgkin's Disease.

Summary A pilot study was begun in 1963 to test the feasibility of using in the treatment of Hodgkin9s disease a combination of cyclophosphamide, vincristine, methotrexate, and prednisone in full doses followed by radiotherapy where indicated. It was found that this form of therapy could be used without a prohibitive cost in toxicity. It appears that the incidence of complete remissions can be increased over that obtained with a single agent. Radiotherapy was tolerated after intensive chemotherapy, and further intensive chemotherapy was possible following high dose but limited field radiation. As expected, toxicity was increased when both modalities of therapy were employed. The duration of complete unmaintained remission in those patients with advanced disease is provocative even though the group is small. It is our feeling that these results invite further investigation of the use of effective agents in combination.

Hematopoietic Cell Transplantation as Curative Therapy for Patients with Myelofibrosis: Long-Term Success in all Age Groups.

Myeloproliferative neoplasms (MPN) are chronic marrow disorders with variable prognoses. Most patients with polycythemia vera, essential thrombocythemia, or even primary myelofibrosis (PMF) are successfully treated with conservative strategies for years or even decades, and recent data suggest that even in patients with high-risk disease, in particular those with PMF, life expectancy can be extended by treatment with janus kinase (JAK2) inhibitors. However, none of those modalities are curative, and after marrow failure develops, the disease "accelerates," or transforms to acute leukemia, the only option able to effectively treat and, in fact, cure MPN is allogeneic hematopoietic cell transplantation (HCT). Outcome is superior if HCT is performed before leukemic transformation occurs. Several reports document survival in unmaintained remission beyond 10years. The most recent analyses show reduced regimen-related mortality (less than 10% or even 5% at day100) and progressively improved survival with both HLA-identical sibling and unrelated donors. The development of low/reduced-intensity conditioning regimens has contributed to the improved success rate and has allowed successful HCT in patients in their seventh and even eighth decade of life. We propose, therefore, that HCT should be offered to fit patients in these age groups and should be covered by their respective insurance carriers.

A multi-center phase II study of high dose IL-2 (HD IL-2) sequenced with vemurafenib in patients with BRAF-V600E mutation positive advanced melanoma.

9053 Background: Durable unmaintained remissions are consistently observed in a small percentage of patients with metastatic melanoma (mM) treated with HD IL-2. Vemurafenib therapy gives rise to a ...

The Use of Registries to Improve Cancer Treatment: A National Database for Patients Treated with Interleukin-2 (IL-2)

Registries evaluating un-randomized patients have provided valuable information with respect to a therapy’s utility, treatment practices, and evolution over time. While immunotherapy for cancer has been around for more than three decades, data collection in the form of a registry has not been undertaken. The authors believe that establishing a registry to study HD IL-2 immunotherapy, which has been the only systemic therapy producing long term unmaintained remissions for advanced kidney cancer and melanoma for over 20 years, will be an important resource in understanding the impact of immunotherapy with HD IL-2 in a rapidly changing therapeutic environment. Optimizing administration and improving selection of appropriate patients likely to benefit from HD IL-2 immunotherapy are two of many benefits to be derived from this endeavor.

Deep Molecular Response Is Reached by the Majority of Patients Treated With Imatinib, Predicts Survival, and Is Achieved More Quickly by Optimized High-Dose Imatinib: Results From the Randomized CML-Study IV

Deep molecular response (MR(4.5)) defines a subgroup of patients with chronic myeloid leukemia (CML) who may stay in unmaintained remission after treatment discontinuation. It is unclear how many patients achieve MR(4.5) under different treatment modalities and whether MR(4.5) predicts survival. Patients from the randomized CML-Study IV were analyzed for confirmed MR(4.5) which was defined as ≥ 4.5 log reduction of BCR-ABL on the international scale (IS) and determined by reverse transcriptase polymerase chain reaction in two consecutive analyses. Landmark analyses were performed to assess the impact of MR(4.5) on survival. Of 1,551 randomly assigned patients, 1,524 were assessable. After a median observation time of 67.5 months, 5-year overall survival (OS) was 90%, 5-year progression-free-survival was 87.5%, and 8-year OS was 86%. The cumulative incidence of MR(4.5) after 9 years was 70% (median, 4.9 years); confirmed MR(4.5) was 54%. MR(4.5) was reached more quickly with optimized high-dose imatinib than with imatinib 400 mg/day (P = .016). Independent of treatment approach, confirmed MR(4.5) at 4 years predicted significantly higher survival probabilities than 0.1% to 1% IS, which corresponds to complete cytogenetic remission (8-year OS, 92% v 83%; P = .047). High-dose imatinib and early major molecular remission predicted MR(4.5). No patient with confirmed MR(4.5) has experienced progression. MR(4.5) is a new molecular predictor of long-term outcome, is reached by a majority of patients treated with imatinib, and is achieved more quickly with optimized high-dose imatinib, which may provide an improved therapeutic basis for treatment discontinuation in CML.

Comparison Of Distant Relapse Rates Of Immune Thromocytopenia In Patients Treated With Steroids Versus Anti-Rh(D) with/Without Steroids Versus Rituximab with/Without Steroids

Background Among therapies for immune thrombocytopenia (ITP) that achieve long unmaintained remissions, distant relapse rates have not been compared. Specific Aims To compare relapse rates following umaintained remissions exceeding 1 year in patients with ITP treated with steroids versus anti-Rh(D) with/without steroids versus rituximab with/without steroids. Methods Institutional Review Board approval was obtained. The charts of 52 consecutive patients with ITP followed in a hematology practice between 07/01/03 and 06/30/13 were reviewed. Remission was defined as a platelet count > 100,000/µL. Patients with the aforementioned treatment and remission characteristics were identified. Steroids were administered alone as dexamethasone 40 mg PO daily for 4 days. Anti-Rh(D) was administered as 75 mcg/kg IV with or without prednisone 60-85 mg PO daily tapered over 4 weeks or dexamethasone 40 mg PO daily for 4 days. Rituximab was administered as 375 mg/m2 IV weekly for 4 weeks or as a single dose with or without dexamethasone 40 mg PO daily for 4 days. Relapse was defined as a platelet count < 30,000/µL. Statistical calculations included ANOVA to compare demographics and chi-square contingency table analysis to compare distant relapse rates (http://www.physics.csbsju.edu/stats). Results There were 16 unmaintained remissions exceeding 1 year in 13 patients following treatment with steroids, anti-Rh(D) with/without steroids, or rituximab with/without steroids. Mean age on presentation, sex ratio, duration of ITP prior to therapy, and duration of follow-up after therapy were similar for the 3 groups (Table 1). Distant relapse rates were 100%, 14.2%, and 66.7% for the steroid, anti-Rh(D) with/without steroid, and rituximab with/without steroid groups, respectively, P = 0.03 (Table 2). Conclusion Among patients who achieve long unmaintained remissions of ITP with steroids, anti-Rh(D) with/without steroids, or rituximab with/without steroids, those treated with anti-Rh(D)-based therapy are the most likely to have extended remission. Disclosures: Off Label Use: Rituximab therapy of ITP.

Adoptive Transfer of Tumor-Infiltrating Lymphocytes in Patients with Metastatic Melanoma: Intent-to-Treat Analysis and Efficacy after Failure to Prior Immunotherapies

Adoptive cell transfer (ACT) using autologous tumor-infiltrating lymphocytes (TIL) was reported to yield objective responses in about 50% of metastatic patients with melanoma. Here, we present the intent-to-treat analysis of TIL ACT and analyze parameters predictive to response as well as the impact of other immunotherapies. Eighty patients with stage IV melanoma were enrolled, of which 57 were treated with unselected/young TIL and high-dose interleukin-2 (IL-2) following nonmyeloablative lymphodepleting conditioning. TIL cultures were established from 72 of 80 enrolled patients. Altogether 23 patients were withdrawn from the study mainly due to clinical deterioration during TIL preparation. The overall response rate and median survival was 29% and 9.8 months for enrolled patients and 40% and 15.2 months for treated patients. Five patients achieved complete and 18 partial remission. All complete responders are on unmaintained remission after a median follow-up of 28 months and the 3-year survival of responding patients was 78%. Multivariate analysis revealed blood lactate-dehydrogenase levels, gender, days of TIL in culture, and the total number of infused CD8+ cells as independent predictive markers for clinical outcome. Thirty-two patients received the CTLA-4-blocking antibody ipilimumab prior or post TIL infusion. Retrospective analysis revealed that nonresponders to ipilimumab or IL-2 based therapy had the same overall response rate to ACT as other patients receiving TIL. No additional toxicities to TIL therapy occurred following ipilimumab treatment. Adoptive transfer of TIL can yield durable and complete responses in patients with refractory melanoma, even when other immunotherapies have failed.

Association of Birthdays with Late Relapses of Immune Thrombocytopenia

Abstract 4685Adult immune thrombocytopenia (ITP) typically takes a chronic or relapsing course. Etiologies of initial presentations and/or late relapses have not been identified. Emotional stress has been associated with adult ITP, but it is not known if there is a causal relationship.1,2 Birthdays have been described as psychosocial stressors that have been linked with vascular events including stroke and myocardial infarction.3 Based on our observation that a disproportionately high number of late relapses were occurring within 3 weeks of patients' birthdays, we conducted a retrospective cohort study to determine if birthdays are associated with the onset and/or late relapses of ITP.Thirty-five consecutive patients with ITP followed between July 1, 2003 through August 11, 2011 were included in the study. Median age at presentation was 48 years (range 22 to 83 yrs). The female:male ratio was 1.9:1. One patient had human immunodeficiency virus. The median duration of follow-up was 28.3 months (range 1.25 to 72 mos). Dates of initial presentation were available for 22 patients. Only 3 (13.6%) presented within 3 weeks of their birthdays. Eleven of 35 patients had a relapse (defined as a platelet count < 30,000/μL or a 50–70% decrease in platelet count from baseline) after an unmaintained remission exceeding 1 year. Four (36%) of these 11 patients had relapses within 3 weeks of their birthdays (binomial test for significance = 0.002). Two of these 4 patients presented 3 weeks following their birthdays, but had noted fatigue 1 week before presenting. Fatigue has been associated with thrombocytopenic exacerbations of ITP;4 these patients therefore were likely relapsing at the onset of fatigue, closer to their birthdays. The other two patients relapsed 3 – 10 days following their birthdays. One was pregnant; pregnancy may have contributed to her relapse. None of the 4 patients had concurrent infections, autoimmune disease, or malignancies.This study is the first to show that birthdays are associated with relapses of ITP after long unmaintained remissions. Birthdays may be accompanied by stress of anticipation, indulgence, and overexertion. Stress is associated with ITP, and may have a causative role in relapsing ITP. Disclosures:No relevant conflicts of interest to declare.

1.3-Bis(2-chloroethyl)-1-nitrosourea(BCNU), cyclophosphamide, vincristine- and prednisone-(BCOP): A new therapeutic regimen for diffuse histiocytic lymphoma

Sixty-seven evaluable patients with mixed cellular and histiocytic lymphomas, both nodular and diffuse, were treated with a combined drug regimen of BCNU, cyclophosphamide, vincristine, and prednisone administered for six monthly courses. Of 28 previously untreated patients with diffuse histiocytic lymphoma, 14 (50%) achieved a complete remission, and an additional 7 (25%) had a good partial response for an overall remission rate of 75%. Complete remissions were also obtained among the small number of mixed and nodular histiocytic lymphomas which were treated. The median survival for previously untreated patients with diffuse histiocytic lymphoma who achieved a complete remission is nearly two years and 42% (8/19) of these patients remain in their initial unmaintained remission (range 2–119 weeks). Hematologic toxicity, although acceptable, was the limiting factor. Granulocytes were more often and more severely depressed than platelets.

I-131-Anti-CD45 Radioimmunotherapy Effectively Targets and Treats T-Cell Non-Hodgkin's Lymphoma

T-cell non-Hodgkin lymphoma (T-NHL) exhibits inferior remission durations and survival rates compared to B-cell NHL. This may be at least partially due to the paucity of targeted therapies and the absence of approved radioimmunoconjugates available for T-NHL. The CD45 antigen is expressed on ~90% of T-NHL and is not readily internalized or shed, making it an appealing target for radioimmunotherapy (RIT). In order to test this hypothesis, we first demonstrated that CD45 was expressed in high copy numbers on the surface of human T-NHL samples and T-NHL cell lines with a median of 3.4×105 CD45 molecules/cell on T-NHL lines (CCRF-CEM, Karpas 299) and 2.25×105 CD45 molecules/cell on patient derived T-NHL specimens (T-LBL, CTCL, NK/T-NHL). We employed an athymic murine xenograft model with the above human T-NHL lines to show that targeting human CD45 could deliver more radioactivity to tumor nodules than to normal tissues. Mice with palpable human T-NHL xenografts were injected with 131I-labeled BC8 (a murine anti-human CD45 antibody [Ab]) and an 125I-labeled murine isotype matched nonbonding control Ab (BHV1). CCRF-CEM xenografts targeted with 131I-BC8 demonstrated 86% (p=.003) and 106% (p=.001) more radioiodine retention at 24h and 48h, respectively, compared to xenografts targeted with the control BHV1 Ab. More importantly, tumor sites exhibited 1.6 (p=.045), 2.4 (p=.008), and 2.7 (p=.007)-fold 131I retention compared to the lungs, liver, and kidneys, respectively (CCRF-CEM, 24h). Similar results were observed at later time points and with other T-NHL lines. We next hypothesized that this preferential tumor targeting would translate into improved tumor control and survival using therapeutic doses of 131I-BC8. Mice with palpable T-NHL xenografts (CCRF-CEM) were randomly assigned to receive 200μg of BC8 labeled with either 300 or 400μCi of 131I, 200μg of BHV-1 (control) labeled with 300μCi 131I, or no treatment. Tumor dimensions and survival were tracked. By day 9, complete remissions (CR) were attained in 90% of mice treated with 400 μCi of 131I-BC8 and 67% of mice that received 300 μCi of 131I-BC8 (Figure). In contrast, none of the untreated control mice or mice that received 300 μCi of 131I-BHV-1 achieved CR (p<0.0001). All 20 mice in the 2 control groups required euthanasia due to tumor growth, whereas only 4 of 20 of the mice in experimental arms needed to be sacrificed due to disease progression and unmaintained remissions persisted for over 72 days following therapy. Since CD45 is also expressed on most normal hematopoietic tissues, we evaluated the ability of anti-CD45 RIT to preferentially localize to tumor and hematolymphoid sites in a syngeneic model targeting murine CD45. Mice with palpable EL-4 (murine T-NHL) xenografts were treated with 200 μg of 131I-30F11 (anti-murine CD45) followed by harvest of tumor sites and normal organs. In this syngeneic model, the ratios of retained radioactivity in tumor sites to critical non-target sites were: lung 5.3 (p<.001), liver 5.4 (p<.001), and kidney 8.7 (p<.001). Comparable ratios were seen when other target sites (marrow, spleen) were compared to normal non-target organs. These data indicate that CD45 is highly expressed on T-NHL, allows reliable antibody targeting of tumor sites in both xenogeneic and syngeneic models, and translates into significantly improved control of T-NHL xenografts.These results support the hypothesis that CD45-targed RIT transplant conditioning regimens may improve outcomes for patients with relapsed/refractory T-NHL. [Display omitted]

A Phase II Trial of Gemcitabine Plus Capecitabine for Metastatic Renal Cell Cancer Previously Treated With Immunotherapy and Targeted Agents

We assessed the clinical activity and safety of gemcitabine plus capecitabine in patients with metastatic renal cell cancer previously treated with immunotherapy. In this phase II trial patients received 1,000 mg/m(2) gemcitabine intravenously on days 1, 8 and 15, plus 830 mg/m(2) capecitabine orally twice daily on days 1 to 21 of 28-day cycles. The primary end point was progression-free survival time. Secondary end points included overall survival time, objective response rate and toxicity. Of 84 patients enrolled 83 were evaluable for response and toxicity. A total of 65 patients had intermediate or poor risk prognosis. Median progression-free survival and overall survival were 4.6 (95% CI 3.7-7.3) and 17.9 months (95% CI 13.2-23.6), respectively. There were 6 partial responses and 1 complete response (objective response rate 8.4% [95% CI 3.5-16.6]). Two patients remain in unmaintained remission close to 3 years from the initiation of gemcitabine plus capecitabine treatment. On multivariate analysis more than 3 disease sites were significantly associated with shorter progression-free survival and patients with thrombocytosis, more than 3 disease sites or anemia had a significantly increased risk of death. Adverse events occurring at least once in more than 5% of patients included grade 3 or greater neutropenia (83%), grade 2 or greater hand-foot syndrome (13%), grade 3 or greater thrombocytopenia (12%), grade 3 or greater thromboembolic events (8%), grade 3 or greater fatigue (8%) and grade 2 or greater mucositis (6%). At the doses and schedule tested gemcitabine plus capecitabine demonstrated modest clinical activity in metastatic renal cell cancer after cytokine failure and produced significant neutropenia. A modified gemcitabine plus capecitabine regimen may be evaluated in patients with metastatic renal cell cancer after failure of approved targeted therapies.

Thalidomide Based Regimens (TBR) for Relapsed/Refractory Multiple Myeloma Patients: Long Term Follow Up, Unmaintained Remissions and Disease Control after Subsequent Treatments.

Introduction: The effectiveness of thalidomide based regimens (TBR) in patients with relapsed/refractory multiple myeloma is well established. However, there are still limited data regarding the long term follow up after such regimens and the outcome of patients when they progress and they receive further treatment. In order to answer these questions we evaluated a series of 114 patients with relapsed/refractory multiple myeloma who were treated with TBR. None of these patients had previously received thalidomide, bortezomib or lenalidomide.Patients and Methods: All patients were treated with thalidomide and dexamethasone with or without other oral agents. More specifically 41 patients had received continuous thalidomide and pulse dexamethasone, 25 patients clarithromycin, continuous thalidomide and pulse dexamethasone, 43 patients intermittent thalidomide, pulse dexamethasone and cyclophosphamide and 5 patients continuous thalidomide, pulse dexamethasone and cyclophosphamide. Type of treatment at the time of progression after TBR, response to this treatment and progression free survival were recorded for each patient. Moreover, patients who received novel agents after progression to TBR, were divided into 2 subgroups, according to their resistance to thalidomide. In group A, patients had refractory or progressive myeloma while on TBR or within 2 months after discontinuation of TBR. In group B, myeloma progressed more than 2 months after discontinuation of TBR.Results: Among the 114 patients, 41 had not responded to TBR and 73 (64%) had achieved at least a partial response. The median PFS for all patients was 8 months. As of June 2007, 10 patients remain without progression from 28 to 81 months (median 54 months). Eight patients remain off treatment and without progression for a median of 56 months (range 28–81). Patients who did not respond to or progressed after TBR were analyzed for further treatment and outcome. Thirty eight patients (37%) died before receiving further treatment, 23 patients (23%) received conventional chemotherapy and 41 patients (40%) received continuous thalidomide and dexamethasone +/− clarithromycin or cyclophosphamide (17 patients), bortezomib and dexamethasone (7 patients), melphalan-bortezomib-dexamethasone and intermittent thalidomide (12 patients) or lenalidomide with dexamethasone (5 patients). Among these 41 patients, 24 were classified in group A (thalidomide resistant) and 17 in group B. Overall 17 (41%) achieved at least partial response after retreatment with novel agent-based regimens. A response was observed in 46% of patients in group A and in 35% of patients in group B. The median progression free survival of the 41 patients who received retreatment with novel agents was 9.2 months and the median survival was 17 months. Among the 23 patients who received conventional chemotherapy only five (21%) patients responded and the progression free survival and the median survival were 5.3 and 10.2 months, respectively.Conclusions: After an oral TBR regimen 6 (5%) patients remain without treatment and free of progression for more than 4 years. A significant number of patients who progressed after TBR and who received further treatment which included a novel agent achieved a response, including several patients who were resistant to TBR.

The Effects of Induction Chemotherapy and High-Dose Melphalan with Tandem Autologous Transplantation in Multiple Myeloma: The Prospective Randomized DSMM 2 Study.

The concept of the DSMM 2 study was to give age-adjusted high-dose treatment to elderly myeloma patients in order to balance efficacy and toxicity. The value of conventional induction chemotherapy before high-dose melphalan and autologous stem cell transplantation and the durability of unmaintaned remissions afterwards was addressed. Between September 2001 and September 2006, 434 multiple myeloma patients 60–70 years of age with 0–1 cycle of pretreatment were recruited from 45 centers. The median age was 65 years. The patients were randomized to receive 4 cycles of conventional induction chemotherapy [A1] (n=216; VAD or idarubicin/Dex in 88%) or no induction chemotherapy [A2] (n=218). Instead of induction chemotherapy, patients in [A2] received only one short course of dexamethasone 40 mg orally (days 1–4 and 8–11). Subsequently, stem cells were mobilized after combination chemotherapy with ifosfamide, epirubicin and etoposide (IEV) followed by G-CSF; stem cells could be collected in 97% of the patients. Then the patients proceeded to tandem MEL140 (melphalan 140 mg/m2) and autologous peripheral blood stem cell transplantation with a time interval between high-dose cycles of 2 months. No consolidation or maintenance treatment was scheduled. Analyses were performed in an intent-to-treat approach. 87% of patients completed the first transplant, 74% the second. Overall, the treatment was well tolerated and grade 3/4 infections and stomatitis after high-dose melphalan occurred in 37% and 9% of patients, respectively. The overall mortality (tumor and/or toxicity) during treatment was 7.1%: 4.5% during the induction phase (6.1% in [A1] versus 2.9% in [A2]), 1.5% after mobilization and 1.1% after high-dose therapy. Notably, the best response (EBMT criteria) at the end of treatment in patients randomized to [A1] (16% CR, 64% PR) or [A2] (18% CR, 69% PR) was not different. An early loss of tumor control with disease progression occurred in 6% in [A1] versus 1% in [A2]. With a median follow-up time of 20 months, there was no significant difference in the median event-free survival (EFS) (22 months in [A1] versus 20 months in [A2]) and not in the overall survival (OS) at 4 years (63% in [A1] versus 65% in [A2]). In ≥ 50% of patients, the time between last treatment and progression was > 16 months. The EFS of patients 60–64 years of age and 65–70 years of age was the same. In conclusion, there was no benefit of conventional induction chemotherapy with VAD- or VAD-like regimens in patients receiving tandem MEL140 with autologous transplantation. This induction treatment therefore may be avoided. Tandem-MEL140 is feasible and well tolerated in the majority of elderly patients with symptomatic myeloma. Its profound and durable anti-tumor effect was demonstrated by prolonged unmaintained remissions. The addition of new agents given as consolidation or maintenance probably will further improve treatment results.

Relationship between Quality of Response to Bortezomib (btz) and Clinical Benefit in Multiple Myeloma (MM) in the APEX and SUMMIT Studies.

BACKGROUND: The phase 2 SUMMIT trial of patients (pts) with relapsed and refractory MM showed that btz (VELCADE®) is active, with a response rate of 27% (CR/PR) as a single agent, median TTP of 7 months, and median OS of 17 months. The phase 3 APEX trial in pts with relapsed MM following 1–3 prior therapies showed btz to be superior to high-dose dexamethasone (dex) in terms of response rate, TTP, and OS. Updated APEX data show a CR/PR rate of 43%, median TTP of 6.2 months, and median OS of 29.8 months. This analysis evaluated the relationship between quality of response to btz (CR/nCR versus PR; PR does not include nCR in this analysis) in these trials and clinical benefit, as defined by treatment-free interval and time-to-alternative-therapy (TFI and TTAT; time from last and first dose of btz, respectively, to first dose of alternative antineoplastic therapy), OS, and TTP.METHODS: In SUMMIT, 202 pts received btz 1.3mg/m2 on days 1, 4, 8, and 11 for up to eight 21-day cycles (median # of cycles: 6). Dex 20mg was added on the day of and day after each btz dose in pts with suboptimal responses to btz alone. In one arm of APEX, 333 pts received btz 1.3mg/m2 on days 1, 4, 8, and 11 for eight 3-week cycles and then on days 1, 8, 15, and 22 for three 5-week maintenance cycles (median # of cycles: 6). Responses in both trials were assessed according to EBMT criteria (modified to include nCR, a CR with positive immunofixation test).RESULTS: Data are shown in the Table. Median TFI appeared longer in pts with CR/nCR vs PR (SUMMIT, 9.8 vs 3.1 months; APEX, 17.5 vs 6.7 months). Similarly, TTAT appeared longer in pts with CR/nCR vs PR (SUMMIT, 15.4 vs 8.5; APEX, 21.2 vs 14.0). Median OS in all response groups has not yet been reached after a median follow-up of 22 months. TTP tended to be longer with CR/nCR vs PR in both studies (SUMMIT, 16.4 vs 9.2; APEX, 12.2 vs 8.3).CONCLUSIONS: Increasing quality of response to btz is associated with greater clinical benefit assessed by extended TFI ,TTAT, and TTP. Long un-maintained remissions can be attained with btz by achieving maximum tumor mass reduction (CR/nCR), even in pts with relapsed/refractory MM. Updated APEX data show that despite rapid initial response, many pts showed continued improvement in terms of M-protein reduction, and an increasing proportion of pts achieved CR with continued therapy. These data, together with the findings of this analysis, support maximizing tumor mass reduction to CR/nCR with btz to achieve greater clinical benefit.Clinical benefit of btz by responseKaplan-Meier median (95% CI)CR/nCRPR*SUMMIT, n1934TFI, mo9.8 (2.7,14.3)3.1 (2.0,8.7)TTAT, mo15.4 (7.9,17.6)8.5 (7.3,14.0)TTP, mo16.4 (10.6,NE)9.2 (7.2,NE)Median cycles, n88APEX, n4887TFI, mo17.5 (6.7,24.1)6.7(4.4,10.0)TTAT, mo21.2 (14.0,27.1)14.0 (12.6,16.1)TTP, mo12.2 (8.8,NE)8.3 (7.6,10.3)Median cycles,† n910*PR does not include nCR in this analysis; †Includes 8 cycles of protocol-specified therapy plus maintenance cycles

Allogeneic Stem Cell Transplantation for Lymphoid Malignancies.

Haematopoietic stem cell transplantation may be curative therapy for selected patients with haematological malignancies. We reviewed our experience in individuals with lymphoid neoplasms (excluding multiple myeloma) who received an allogeneic stem cell transplant from HLA identical sibling donors. Myeloablative conditioning was radiation based (n= 46) or with chemotherapy (n= 12). GvHD prophylaxis was with T-cell depletion (CAMPATH-1 g or H,“ in the bag”). 17 received a BMT while 41 had PBPC (median CD34+ 2.64). Patients receiving BMT had no further immunosuppression, while 12 patients who received PBPC grafts received prednisone 30 mg and another 21 were treated with therapeutic doses of cyclosporine for 90 days. The diagnosis was indolent lymphoma in 14 (median 3 treatment modalities), aggressive variant in 18 (7 with transformed DLBC; 6 with lymphoblastic lymphoma, 2 mantle cell), 5 had chemotherapy responsive (median 4 treatments) recurrent Hodgkin's lymphoma and 21 had lymphoblastic leukaemia (18 in CR1). Median age was younger in patients with ALL (24 years; range 15–45) than lymphoma (47 years; 29–57; p< 0.001). At a median follow up of 1173 (32–5598) days, 20 have died and 67% survive disease free. Death was from disease recurrence in 15 (10 with ALL), and it was transplant related in 4 while one patient died of AIDS. Survival was significantly worse in patients with lymphoblastic leukaemia (48%; p< 0.001), while 76% of those with lymphomas survive in unmaintained remission (median 1493 days; 32–5598). Survival was significantly associated with diagnosis of lymphoma (p< 0.01), CD34+ cell number above median (p= 0.04) and absence of GvHD (p< 0.01). We conclude that despite T-cell depletion allogeneic stem cell transplantation is very effective therapeutic strategy in patients with lymphoma, as disease recurrence was low (relapse 6/37; p= 0.03), suggesting remaining graft vs. lymphoma effect. To the contrary, this therapy remains less satisfactory for patients with ALL who have poor prognostic factors.

Current Treatment Approaches for Mantle-Cell Lymphoma

Mantle-cell lymphoma (MCL) is now recognized as a distinct clinicopathologic subtype of B-cell non-Hodgkin's lymphoma. Patients with MCL are typically older adults with a male predominance and usually present with stage IV disease. The cells are characterized as CD20+ CD5+ CD23- with a t(11;14)(q13;q32) and cyclin D1 overexpression on immunohistochemistry. Response to chemotherapy usually results in a tumor response but unmaintained remissions are short and the median survival is 3 to 4 years. The treatment approach to newly diagnosed patients with MCL depends on the patient's eligibility for stem cell transplantation (SCT). Those who are eligible are usually treated with either rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by SCT or rituximab-HyperCVAD (cyclophosphamide, vincristine, doxorubicin, decadron, cytarabine, and methotrexate) followed by observation. The purine nucleoside analogues also have activity as single agents and with rituximab. Unfortunately none of these approaches can definitively cure patients with MCL, and new agents are needed. Recent studies in patients with relapsed MCL have shown substantial antitumor activity of single-agent bortezomib, single-agent temsirolimus, and the combination of thalidomide and rituximab. Studies integrating these novel agents earlier in the disease course or in combination with each other will hopefully produce more durable responses with less toxicity.