Among prognostic factors for chronic lymphocytic leukemia (CLL), immunoglobulin heavy chain variable region (IGHV) mutation status and DNA analysis appear to be the most important. However, there is limited clinical outcome information for patients with the favorable-risk del(13q) and poor-risk unmutated IGHV. We retrospectively screened all patients with CLL at our institution between 2004 and June 2010 for del(13q) who also had an IGHV analysis. Unmutated IGHV was found in 38/79 patients; age, Rai stage, prior therapy, and time to evaluation were similar to those for patients with mutated IGHV. Unmutated patients were nearly four times more likely to harbor additional chromosomal aberrations compared to mutated patients (p < 0.001). During a median follow-up of 4.5 years, unmutated patients were more likely to demonstrate Rai stage progression (69% vs. 31%, log-rank p < 0.001) and to receive treatment (5-year cumulative probability of treatment: 65% vs. 32%, p < 0.001). Patients with unmutated CLL also had a shorter overall survival (5-year survival probability: 72% vs. 100%, p < 0.001). When limiting analysis to the 47 patients with del(13q) as a sole chromosomal abnormality, the 13 (28%) unmutated patients were more likely to demonstrate Rai progression (p < 0.001), to receive treatment (P = 0.02), and to have a shorter overall survival (P = 0.13) than the 34 mutated patients. These data suggest that del(13q) conveys an indolent course only in patients with IGHV-mutated CLL.
CLL; del(13q); IGHV; clinical outcomes; overall survival
Autologous stem cell transplant (ASCT) is an effective treatment for multiple myeloma (MM). However the timing of ASCT in the era of novel agents (lenalidomide, thalidomide, bortezomib) is unknown. We retrospectively reviewed the outcome of MM patients who received novel agent based induction treatment and received first ASCT within 12 months of diagnosis (early ASCT, N = 102), or at a later date (late ASCT, N = 65). Median time to ASCT was 7.9 months vs. 17.7 months in the early vs. late ASCT. The 3 and 5 yr overall Survival (OS) from diagnosis was 90 and 63% versus 82 and 63% in early and late ASCT respectively (P=0.45). Forty-one and 36 patients in the early and late ASCT have relapsed or progressed with median time to relapse of 28 and 23 mos (p=0.055). On multivariable analysis, factors predictive of increased risk for progression were ISS stage III (p=0.007), and < VGPR post-ASCT (p<0.001). Factor predictive of worst outcomes for OS was being on hemodialysis (p=0.037). No superiority of one agent was seen. In summary, early or late ASCT is a viable option for MM patients receiving induction treatment with novel targeted therapies.
Multiple Myeloma; Transplantation; Bortezomib; Lenalidomide
Statins are HMG-CoA reductase inhibitors, which block the conversion of HMG-CoA to mevalonate and have potent cholesterol lowering properties. Beyond their importance in generation of lipid lowering effects, the regulatory effects of statins on the mevalonate pathway have significant impact on multiple other cellular functions. There is now extensive evidence that statins have anti-inflammatory and anti-neoplastic properties, but the precise mechanisms by which such responses are generated are not well understood. In the present study we demonstrate that statins engage a member of the PKC family of proteins, PKCδ, in acute promyelocytic leukemia (APL) cells. Our studies show that atorvastatin and fluvastatin induce proteolytic activation of PKCδ in the APL NB4 cell line which expresses the t(15;17) translocation. Such engagement of PKCδ results in induction of its kinase domain and downstream regulation of pathways important for statin-dependent leukemia cell differentiation. Our studies show that the function of PKCδ is essential for statin-induced leukemic cell differentiation, as demonstrated by studies involving selective targeting of PKCδ using siRNAs. We also demonstrate that the potent enhancing effects of statins on ATRA-induced gene expression for CCL3 and CCL4 requires the function of PKCδ, suggesting a mechanism by which statins may promote ATRA-induced antileukemic responses. Altogether, our data establish a novel function for PKCδ as a mediator of statin-induced differentiation of APL cells and antileukemic effects.
The impact of mutation of the ATM (ataxia telangiectasia mutated) gene in chronic lymphocytic leukemia (CLL) treatment outcome has not been examined. We studied ATM mutations in 73 patients treated with fludarabine and rituximab. ATM gene mutation analysis was performed using temperature gradient capillary electrophoresis. The impact of detected variants on overall survival (OS) and progression-free survival (PFS) was tested with proportional hazards models. None of the 73 patients demonstrated truncating ATM mutations; 17 (23%, 95% confidence interval 14 – 35%) had non-silent variants (ATM-NSVs), including 13 known ATM polymorphisms and four missense variants. ATM-NSVs were not significantly associated with any baseline characteristics including immunoglobulin heavy chain variable gene (IGVH) status. In multivariable models, no significant differences in complete response (p = 0.70), PFS (p = 0.59) or OS (p = 0.13) were observed. Our data indicate that truncating ATM mutations are rare in patients with CLL. Furthermore, in this dataset, these non-silent variants had limited impact on PFS and OS.
Chronic lymphocytic leukemia; ATM mutation; prognosis; chemoimmunotherapy
A number of antibodies have been developed that induce lethal iron deprivation (LID) by targeting the transferrin receptor 1 (TfR1/CD71) and either neutralizing transferrin (Tf) binding, blocking internalization of the receptor and/or inducing its degradation. We have developed recombinant antibodies targeting human TfR1 (ch128.1 and ch128.1Av), which induce receptor degradation and are cytotoxic to certain malignant B-cells. We now show that internalization of TfR1 bound to these antibodies can lead to its sequestration and degradation, as well as reduced Tf uptake, and the induction of a transcriptional response consistent with iron deprivation, which is mediated in part by downstream targets of p53. Cells resistant to these antibodies do not sequester and degrade TfR1 after internalization of the antibody/receptor complex, and accordingly maintain their ability to internalize Tf. These findings are expected to facilitate the rational design and clinical use of therapeutic agents targeting iron import via TfR1 in hematopoietic malignancies.
Transferrin; antibody; iron deprivation
Established cell lines are utilized extensively to study tumor biology and preclinical therapeutic development; however, they may not accurately recapitulate the heterogeneity of their corresponding primary disease. B-cell tumor cells are especially difficult to maintain under conventional culture conditions, limiting access to samples that faithfully represent this disease for preclinical studies. Here, we used primary canine diffuse large B-cell lymphoma to establish a culture system that reliably supports the growth of these cells. CD40 ligand, either expressed by feeder cells or provided as a soluble two-trimeric form, was sufficient to support primary lymphoma cells in vitro. The tumor cells retained their original phenotype, clonality and known karyotypic abnormalities after extended expansion in culture. Finally, we illustrate the utility of the feeder cell-free culture system for comparable assessment of cytotoxicity using dog and human B-cell malignancies. We conclude this system has broad applications for in vitro preclinical development for B-cell malignancies.
Diffuse large B-cell lymphoma; CD40L; Primary cell culture; Canine model; Cytotoxicity assay
Large granular lymphocyte (LGL) leukemia is a rare disorder of cytotoxic lymphocytes. LGL cells play an integral role in the immune system and are divided into two major lineages of CD3− natural killer (NK) cells and CD3+ T cells that circulate throughout the blood in search of infected cells, in which they will make contact through a receptor ligand and induce cell death. LGLs cells are also programmed to undergo apoptosis after contact with an infected target cell; however they continue to survive in individuals with LGL leukemia. This unchecked proliferation and cytotoxicity of LGLs in patients results in autoimmunity or malignancy. Rheumatoid arthritis is the most common autoimmune condition seen in individuals with LGL leukemia; however, LGL leukemia is associated with a wide spectrum of other autoimmune diseases. Patients may also suffer from other hematological conditions including hemolytic anemia, pure red cell aplasia, and neutropenia which lead to recurrent bacterial infections. Currently, the only established treatment involves a low dose of an immunosuppressive regimen with methotrexate, in which 40–50% of patients are either resistant or do not respond. In order to establish new therapeutics it is important to understand the current state of LGL leukemia both in clinic and in basic research.
Lymphocytes; NK cell biology; lymphoid leukemia
Azacitidine and decitabine are two hypomethylating agents approved by the Food and Drug Administration for the treatment of patients with myelodysplastic syndrome (MDS). The efficacy of one agent post failure of the other is unknown.
Fourteen patients with MDS post azacitidine failure/lack of response/intolerance were treated with decitabine.
Overall 3 patients achieved a complete remission and 1 patient had hematologic improvement, for an overall response rate of 28%. Of the responders 1 stopped prior 5-azacitidine due to disease progression, 2 for no response and l for severe skin toxicity. Grade 3-4 drug related side-effects were minimal. Global methylation studies in patient samples showed decrease of methylation after treatment with decitabine. As in our previous studies, there was no difference in hypomethylation between responders and non-responders.
We conclude that clinically significant responses with decitabine can be seen in patients post azacitidine failure without significant toxicity.
azacitidine failure; decitabine; myelodysplastic syndrome
The use of nucleoside analog-based chemoimmunotherapeutic regimens over the last decade has significantly improved outcomes in patients with chronic lymphocytic leukemia (CLL). Nonetheless, virtually all patients with CLL relapse from chemoimmmunotherapy and current available therapies are not curative. Identifying therapies that effectively eliminate CLL cells and lack immunesuppression represent an exciting new therapeutic approach. IMiDs are a class of immunomodulating drugs that increase T-cell and NK-cell directed killing of tumor cells. The first generation molecule is thalidomide followed by a second generation molecule lenalidomide that lacks neurotoxicity and is being explored more extensively in clinical trials. Lenalidomide has been shown to benefit patients with multiple myeloma, myelodysplastic syndromes, and lymphoma. Initial reports in patients with relapsed and refractory CLL have shown promising responses. In a subset of patients with CLL complete responses have been noted. Subsequent studies, however, have suggested that this class of drug can also have serious and potentially life-threatening side effects including myelosuppression, tumor flare reaction and in a small subset of patients tumor lysis syndrome. Tumor flare with both thalidomide and lenalidomide appear to be disease specific to CLL and may reflect clinical manifestation of CLL tumor cell activation. As a consequence of these disease specific effects, the optimal safe dose of lenalidomide in CLL remains to be determined but appears to be lower than that tolerated in other B-cell malignancies. To date, biomarkers for response remain poorly defined and the relationship of clinical benefit to tumor flare is uncertain. This review examines the existing literature on the use of IMiDs in patients with CLL and provides suggestions for future research in this area.
Chronic lymphocytic leukemia; thalidomide; lenalidomide; tumor flare reaction; tumor lysis syndrome
We evaluated the safety and efficacy of the purine nucleoside analogue, clofarabine, in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). Six patients with DLBCL (n = 5) or MCL (n = 1) and a median age of 68 years were treated with 40 mg/m2 clofarabine IV over 2 h for 5 days, repeated every 28 days, for 1–2 cycles. The overall response rate was 50% (complete response = 1, complete response unconfirmed = 1, partial response = 1). Median progression-free survival was 3.5 months (range 1.5–10 months) and the median overall survival was 7.8 months (range 3–31 months). Grade 3–4 neutropenia and thrombocytopenia was universal, with a median of 34 (range 19–55) and 77 (range 0–275) days required for neutrophil and platelet recovery. Grade 3 non-hematologic toxicities included transaminitis, febrile neutropenia, non-neutropenic infections and orthostatic hypotension. Further accrual to the study was terminated due to prolonged Grade 3–4 myelosuppression and orthostatic hypotension in five of six patients. Clofarabine exhibits evidence of single agent activity in relapsed or refractory DLBCL. However, further study with novel administration schedules that maintain this efficacy and limit toxicity is warranted.
Clofarabine; diffuse large B cell lymphoma; mantle cell lymphoma; nucleoside analogues; myelosuppression
Anti-B4-blocked ricin (anti-B4-bR) is a potent immunotoxin directed against the CD 19 antigen. Previous phase I and II studies suggested a possible role for anti-B4-bR as consolidation after high-dose chemotherapy and autologous stem cell transplant. Cancer and Leukemia Group B (CALGB) 9254 is a phase III study which randomized 157 patients with B-cell lymphoma in complete remission following autologous transplant to treatment with anti-B4-bR or observation. With a median follow-up time for patients of 5.8 years, the median event-free survival for protocol treatment and observation are 2.1 and 2.9 years, respectively (p = 0.275). The median overall survival for treatment and observation are 6.1 years and not reached, respectively (p = 0.063). Therefore, no differences were found in event-free survival and overall survival between protocol treatment and observation, although there was a trend toward improved survival with observation. These data fail to support a role for anti-B4-bR as consolidative therapy after bone marrow transplant in patients with B-cell lymphoma.
Lymphoma; anti-B4-blocked ricin; autologous transplant; adjuvant therapy
Pneumonitis is a complication of high-dose chemotherapy and autologous stem cell transplantation (HDC-ASCT) regimens containing BCNU. Our goal was to define the incidence and risk factors for pneumonitis in lymphoma patients receiving a uniform conditioning regimen in the modern era. We studied 222 patients who received HDC-ASCT using cyclophosphamide, BCNU, and VP-16 (CBV). Pneumonitis incidence was 22%, with 19% receiving systemic corticosteroid treatment, and 8% requiring inpatient hospitalization for pneumonitis. Three patients died secondary to pneumonitis-related complications. The following variables were independently associated with pneumonitis: prior mediastinal radiation (odds ratio 6.5, 95%CI 2.3–18.9, P=0.0005), total BCNU dose above 1000 mg (OR 3.4, 95%CI 1.3–8.7, P=0.012), and age less than 54 (OR 3.0, 95%CI 1.4–6.5, P=0.0037). Increased vigilance for symptoms of pneumonitis is warranted for patients with prior mediastinal radiation and for younger patients, and dose reduction may be considered for patients who would receive greater than 1000 mg of BCNU.
Both LMO2 mRNA and protein expression in diffuse large B-cell lymphoma (DLBCL) have been associated with superior survival; however, a role for germline genetic variation in LMO2 has not been previously reported. Immunohistochemistry (IHC) for LMO2 was conducted on tumor tissue from diagnostic biopsies, and 20 tag single nucleotide polymorphisms (SNPs) from LMO2 were genotyped from germline DNA. LMO2 IHC positivity was associated with superior survival (HR=0.55; 95% CI 0.31–0.97). Four LMO2 SNPs (rs10836127, rs941940, rs750781, rs1885524) were associated with survival after adjusting for LMO2 IHC and clinical factors (p<0.05), and one of these SNPs (rs941940) was also associated with IHC positivity (p=0.02). Compared to a model with clinical factors only (c-statistic=0.676), adding the 4 SNPs (c-statistic=0.751) or LMO2 IHC (c-statistic=0.691) increased the predictive ability of the model, while inclusion of all 3 factors (c-statistic=0.754) did not meaningfully add predictive ability above a model with clinical factors and the 4 SNPs. In conclusion, germline genetic variation in LMO2 was associated with DLBCL prognosis and provided slightly stronger predictive ability relative to LMO2 IHC status.
Diffuse large B-cell lymphoma; LMO2; prognosis; single nucleotide polymorphisms
Quality of life (QoL) is an important outcome in patients with non-Hodgkin lymphoma (NHL). We assessed the validity of administering the Functional Assessment of Cancer Therapy – General (FACT-G) at 12-month intervals over 3 years in a longitudinal study of 611 prospectively enrolled, newly diagnosed NHL patients. We evaluated corrected item-total correlation and percent missing to identify items that may be less useful in certain NHL patient subgroups. The FACT-G subscales and total score demonstrated good internal consistency reliability, convergent validity and known-groups validity. Most scores also demonstrated good responsiveness to change. Questions that could be problematic included GE3 (losing hope) and GP2 (nausea) for patients in remission, and GP5 (bothered by side effects) for patients being observed. Overall, the FACT-G was a valid measure for monitoring QoL over time in NHL patients. However, sensitivity analyses based on subscale scoring that excludes potentially problematic items may be warranted.
non-Hodgkin lymphoma; quality of life; validation studies; patient-reported outcomes
The impact of rituximab on outcome of high dose therapy and autologous stem cell transplantation (HD-ASCT) for transformed NHL has not been previously described. We analyzed eighteen consecutive patients with indolent NHL who transformed to diffuse large B-cell lymphoma (DLBCL), received rituximab-containing therapy either before or after transformation and underwent subsequent HD-ASCT. With a median follow-up of 40 months, the 2-year PFS was 59% and the 2-year OS was 82%. Six patients did not receive rituximab pre-transformation; this group had a significantly better PFS at 2 years post HD-ASCT compared to 12 patients who were exposed to rituximab pre-transformation (p=0.03). HD-ASCT remains an effective therapeutic option for transformed NHL in the rituximab era. However, patients exposed to rituximab pre-transformation appear to have inferior HD-ASCT outcomes, and thus may benefit from novel conditioning and maintenance regimens in the setting of HD-ASCT.
HD-ASCT; Transformed NHL; Rituximab; Transplant
Natural killer (NK) cells can be engineered to kill resistant B-lymphoid cell lines and primary B-cell chronic lymphocytic leukemia (B-CLL) cells after transfection with chimeric antigen receptors (CARs) recognizing CD19 or CD20. Here we compared mRNA electroporation with lentiviral vector (LV) transduction for both CARs. Transfection efficiency and cytotoxicity of previously NK-92 resistant CLL cells were significantly higher after mRNA electroporation than after LV transduction. Further cell sorting of LV-transduced NK-92 cells resulted in a highly enriched population of transduced cells with significant target cell lysis. Compared to NK-92 cells, peripheral blood and cord blood cells consistently showed < 10% transfection efficiency with mRNA, while LV transduction varied between 8 and 16% for peripheral blood and 12 and 73% for cord blood. These results suggest that LV should be used to achieve sufficient transgene expression if blood NK cells are considered for CAR transduction. Transfection with mRNA results in clinically relevant levels of transfection only in NK-92 cells.
CAR; lymphoid malignancies; NK cells; lentiviral vector
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the treatment of choice for patients with chronic myelogenous leukemia (CML) who have failed or are intolerant to tyrosine kinase inhibitors (TKI). Myeloablative conditioning regimens have been associated with high treatment-related mortality (TRM) rate in such patients, and reduced-intensity conditioning (RIC) regimens are often preferred but have high rates of disease recurrence and graft-versus-host-disease (GVHD). We report our experience with nine CML patients (four chronic phase and five with accelerated phase or blast crisis) who failed TKI and underwent allo-HSCT using an alemtuzumab-based RIC regimen. The conditioning regimen was well tolerated and induced engraftment in all patients, and complete cytogenetic remission (CCyR) in eight of nine. Four patients, all with a history of accelerated phase or blast crisis, died. Four of the five remaining patients had a cytogenetic relapse a median of 10 months after transplantation. Donor lymphocyte infusion (DLI), TKI or both induced a CCyR in all cases. With a median follow-up of 47 months, five patients, including all those transplanted in first or second chronic phase, are alive and in remission. Allo-HSCT with an alemtuzumab-based conditioning regimen induces remission in patients with CML that have failed TKI therapy and has a low incidence of GVHD. Disease recurrence is frequent but responds to DLI. In some cases, restoration of susceptibility to TKI was observed. Outcomes may improve with the routine administration of post-transplant TKI.
Chronic myelogenous leukemia; reduced-intensity conditioning; alemtuzumab; tyrosine kinase inhibitors
We analyzed 67 patients with lymphoma who received alemtuzumab-based conditioning regimens for allogeneic stem cell transplant and no post-transplant DLI. The median age was 54 (24–70), 43% had unrelated donors, 34% had chemotherapy refractory disease, and 25% had an elevated LDH. With a median follow-up for survivors of 35 months, the estimated 3-year progression-free survival (PFS) and overall survival (OS) were 30% and 47%, respectively. Chemosensitivity by CT and pre-transplant LDH were independent prognostic factors for both overall survival and progression-free survival. Patient age, performance status, donor type, lymphoma subtype, disease sensitivity by PET, and conditioning regimen did not correlate with PFS and OS. Patients who relapsed greater than 6 months after allogeneic transplant were frequently able to re-enter a subsequent durable remission. Our experience confirms the curative potential of alemtuzumab-containing RIC regimens for allogeneic HCT in patients with relapsed lymphoma without prophylactic DLI. An elevated pre-transplant LDH and chemorefractory disease prior to transplant confer a worse prognosis, while PET scan findings do not have this same implication. Patients who relapse greater than 6 months after their transplant are likely to achieve a subsequent remission with any of a variety of interventions, suggesting that GVL effects can be operative even after recurrence. Our outcomes challenge the utility of the common practice of prophylactic DLI after T-depleted transplant for lymphoma.
Lymphoma; Alemtuzumab; Allogeneic HCT; LDH; Chemosensitivity
CTCL is responsive at all stages to immunotherapy. We determined whether a novel agonist for TLR 7/8 (3M007) combined with either IFN-γ or IL-15 enhanced patients' immune responses in vitro. Our data demonstrate synergism between IFN-γ and 007 in the activation of patients' NK cytolytic activity against CTCL tumor cell lines and increased production of cytokines by dendritic cells compared to 007 alone. Microarray studies of gene expression of patients' PBMC primed with IFN-γ followed by stimulation with 007 identified significant upregulation of expression of IL-12- p35 (α-chain), IL-12-p40 (β-chain) and nine IFN-α genes. Importantly, the underlying mechanism of increased levels of IFN-α and IL-12 from combined treatment appears to involve IFN regulatory factor 8 (IRF-8). These results further support our hypothesis that combinations of biological modifiers activating different arms of the immune system may provide significant therapeutic benefits for patients with advanced CTCL.
CTCL; immunotherapy; TLR7/8 agonist; IFN-γ; IRF-8
Anthracycline-based chemotherapy (ABC) is the most effective therapy for diffuse large B-cell lymphoma (DLBCL). The addition of rituximab to ABC in controlled trials has demonstrated superior survival, yet ABC is inconsistently utilized in elderly patients, and little is known about the penetrance or impact of rituximab with other treatments. We analyzed the treatment and survival patterns of 7559 patients with DLBCL over age 66 diagnosed from 1992 to 2002 using a linked Surveillance, Epidemiology and End Results (SEER)–Medicare database. Rituximab use was first detected in 1999 and by 2002 was incorporated in 79% of ABC-treated patients and 71% of patients treated with non-anthracycline chemotherapy, but only 12% of patients not receiving cytotoxic chemotherapy. ABC rates remained constant across time as did rates of no therapy, which were highest among the very old. Rituximab-associated survival improvements were seen among elderly treated with or without anthracyclines. Patients treated with rituximab but not anthracyclines had comparable survival to those treated with anthracycline but not rituximab.
Non-Hodgkin lymphoma; immunotherapy; survival; elderly
Pediatric nodal marginal zone lymphoma (NMZL) is described as a separate variant of NMZL in the most recent WHO classification of tumors of hematologic and lymphoid tissues. It has distinctive morphology and clinical presentation and stands out as an indolent disease with remarkably better overall prognosis compared to classic NMZL. Here we report two adult cases of NMZL with clinical and morphologic features consistent with pediatric NMZL (pNMZL) and review available literature describing the clinical and histologic presentation of pNMZL.. Two men, ages 44 and 18 years, each presented with localized cervical lymphadenopathy that histologically demonstrated florid proliferation of the marginal zone and disruption of reactive germinal centers, progressive transformation of germinal centers (PTGC) -like morphologic features typical for pNMZL and clonal disease with immunophenotype consistent with NMZL. This is the first report of pNMZL in a middle-aged person. Distinct histologic features and characteristic benign clinical course will help to distinguish this rare variant from other NMZL in adults. Clinically, recognition is important to understand the true incidence of this rare form in the adult population and to avoid unnecessary overtreatment of this indolent form.
lymphoma; lymphoid malignancies; marginal zone lymphoma; B cell; pediatric malignancy; adult
The purpose of this study was to determine the activity of topotecan given by 21-day continuous infusion in patients previously treated with one prior therapy for a diffuse large cell lymphoma or immunoblastic lymphoma. Patients with appropriate histology and measurable disease who had been treated with one prior chemotherapy regimen were eligible for study. Slides of tumor biopsies were submitted for central review of pathology. Patients were required to have ECOG performance status of 0, 1, or 2 and adequate bone marrow function. Patients were treated with continuous infusion topotecan, 0.4 mg/m2/day × 21 days. Therapy could be escalated to 0.5 and then 0.6 mg/m2/day in subsequent cycles if there was no dose limiting toxicity at the initial dose level. Patients were treated with 2 cycles after achieving complete response or until disease progression or unacceptable toxicity occurred. Thirty seven patients were enrolled, however, only 26 cases were eligible due to performance status of > 2 (2), more than one prior chemotherapy (1), and wrong histology on review (8). Due to the unexpectedly high ineligibility rate, two sets of analysis were done for all the 37 patients enrolled and for the 26 eligible patients, respectively. Of the 37 patients (15 males and 22 females), international prognostic index included 11% low risk, 30% low-intermediate risk; 46% high-intermediate risk, and 8% high risk. The median follow up was 77 months. A total of 136 cycles of therapy were given with a median of 3 cycles per patient. Grade 4 toxicities included: 14% grade 4 thrombocytopenia; 14% grade 4 granulocytopenia, 8% leukopenia, 3% each anemia, hemorrhage, infection, vomiting, thrombosis, liver toxicity, and neuromotor toxicity. The response analysis including all 37 patients showed 5 complete remissions (CR) and 4 partial remissions (PR) for a total response rate of 24% (90% two-stage confidence interval 13–39%). Median progression free survival (PFS) was 3.7 months, with one and two year PFS of 21% and 6% respectively (90% confidence interval 11–34% and 2–15%). Median overall survival (OS) was 10.5 months, with one and two year OS 41% and 27% respectively (90% confidence interval 27–53% and 16–39%). Analysis including only eligible patient showed similar response rates and survival outcomes. Single agent topotecan has moderate activity for previously treated high grade lymphoma equivalent to that of several newer agents, and should be considered for incorporation into multi-drug salvage chemotherapy programs.
We performed a phase II study of oral vorinostat (200 mg twice daily, days 1–14 of a 21-day cycle), to examine efficacy and tolerability in patients with relapsed/refractory hodgkin lymphoma (HL) with ≤ 5 prior therapies. The primary endpoint was objective response rate (ORR), with secondary endpoints of progression-free survival (PFS), overall survival (OS), safety and tolerability. A two-stage design was used for patient accrual. Twenty-five eligible patients were accrued in the first stage. Median time on treatment was 3.8 months. ORR was 4% (1 partial response). Median PFS was 4.8 months. The drug was well tolerated. The second stage of accrual was not opened due to few objective responses. Oral vorinostat has limited single agent activity in relapsed/refractory HL. There was one partial response, while seven other patients had stable disease for > 1 year, including 2 with stable disease for nearly 3 years, suggesting that further studies in combination with other active agents in this setting may be warranted.
MM is the top indication for high-dose chemotherapy (HDC) with autologous stem cell transplantation (SCT), a strategy which improves progression-free survival and potentially overall survival. Novel induction regimens incorporating the immunomodulatory (IMID) agents thalidomide and lenalidomide, and the proteosome inhibitor bortezomib improve response rates and survival for newly diagnosed patients. Recent data temper enthusiasm for these treatments by illustrating difficulty in some circumstances with mobilizing CD34(+) hematopoietic stem cells for subsequent HDC/SCT. We compare conventional induction regimens with novel-agent based induction strategies and the associated effects on stem cell mobilization and HDC/SCT outcome in 397 patients. Although patients exposed to novel agent inductions collected generally fewer CD34(+) cells than patients induced with chemotherapy, these differences did not translate into adverse consequences with subsequent HDC/SCT. We show that an improvement in overall survival following HDC/SCT may be related to induction therapy with novel agents as opposed to chemotherapy. Our data extrapolate on prior work and expand on ongoing controversies about optimal induction regimens for MM patients planned for subsequent HDC/SCT and optimal sequencing of therapies.
Multiple myeloma; stem cell transplant; stem cell mobilization