David L. Grinblatt

Thalidomide has limited single-agent activity in relapsed or refractory indolent non-Hodgkin lymphomas : a phase II trial of the Cancer and Leukemia Group B

Thalidomide is an immunomodulatory agent with demonstrated activity in multiple myeloma, mantle cell lymphoma and lymphoplasmacytic lymphoma. Its activity is believed to be due modulation of the tumour milieu, including downregulation of angiogenesis and inflammatory cytokines. Between July 2001 and April 2004, 24 patients with relapsed/refractory indolent lymphomas received thalidomide 200 mg daily with escalation by 100 mg daily every 1–2 weeks as tolerated, up to a maximum of 800 mg daily. Patients had received a median of 2 (range, 1–4) prior regimens. Of 24 evaluable patients, two achieved a complete remission and one achieved a partial remission for an overall response rate of 12·5% (95% confidence interval: 2·6–32·4%). Eleven patients progressed during therapy. Grade 3–4 adverse effects included myelosuppression, fatigue, somnolence/depressed mood, neuropathy and dyspnea. Of concern was the occurrence of four thromboembolic events. Our results failed to demonstrate an important response rate to single agent thalidomide in indolent lymphomas and contrast with the higher activity level reported with the second generation immunomodulatory agent, lenalidomide.

Real-world clinical experience in the Connect(®) chronic lymphocytic leukaemia registry: a prospective cohort study of 1494 patients across 199 US centres.

The clinical course of chronic lymphocytic leukaemia (CLL) is heterogeneous, and treatment options vary considerably. The Connect® CLL registry is a multicentre, prospective observational cohort study that provides a real‐world perspective on the management of, and outcomes for, patients with CLL. Between 2010 and 2014, 1494 patients with CLL and that initiated therapy, were enrolled from 199 centres throughout the USA (179 community‐, 17 academic‐, and 3 government‐based centres). Patients were grouped by line of therapy at enrolment (LOT). We describe the clinical and demographic characteristics of, and practice patterns for, patients with CLL enrolled in this treatment registry, providing patient‐level observational data that represent real‐world experiences in the USA. Fluorescence in situ hybridization (FISH) analyses were performed on 49·3% of patients at enrolment. The most common genetic abnormalities detected by FISH were del(13q) and trisomy 12 (45·7% and 20·8%, respectively). Differences in disease characteristics and comorbidities were observed between patients enrolled in LOT1 and combined LOT2/≥3 cohorts. Important trends observed include the infrequent use of genetic prognostic testing, and differences in patient characteristics for patients receiving chemoimmunotherapy combinations. These data represent experiences of patients with CLL in the USA, which may inform treatment decisions in everyday practice.

Patients with myelodysplastic syndromes treated with azacitidine in clinical practice: the AVIDA® registry

Abstract The AVIDA registry evaluated azacitidine usage and effectiveness in unselected patients with myelodysplastic syndromes (MDS) in community practice. Treating physicians made all treatment decisions. Hematologic improvement (HI) and transfusion independence (TI) assessments used International Working Group (IWG) 2000 criteria. Enrolled were 421 patients with MDS (n = 228 International Prognostic Scoring System [IPSS] lower-risk, n = 106 higher-risk, 86 patients unclassified) from 105 US sites. Median follow-up was 7.6 months (range: 0.1–27.6). HI and red blood cell TI rates were similar regardless of administration route or dosing schedule. Safety and tolerability were consistent with previous reports. The AVIDA registry data support azacitidine effectiveness and safety in patients with lower- or higher-risk MDS treated in community practice.

Autologous and allogeneic transplantation for aggressive NHL

BACKGROUND Intermediate- and high-grade NHL are generally chemosensitive diseases with high initial response rates to combination chemotherapy. Dose intensification via autologous and allogeneic transplantation provides viable treatment options in specific clinical settings. Currently, autologous transplantation is the standard of care for relapsed but chemosensitive aggressive B-cell NHL. However, tools such as the International Prognostic Index allow risk-adapted analyses, and show that the magnitude of benefit from autologous transplantation differs in lymphoma subsets. METHODS Low-risk patients appear to do well regardless of salvage approaches, whereas high-risk patients have suboptimal outcomes with autologous transplantation. In high-risk patients, high-dose chemotherapy with autologous stem-cell transplantation has been examined as part of initial therapy, with long-term data promising but still evolving. DISCUSSION A significant concern with autologous transplantation in aggressive and high-grade NHL is the risk of graft contamination with tumor cells. Several investigators have demonstrated the presence of malignant cells in both BM and PBSC, although the clonagenic potential of such cells is unclear. Allogeneic stem-cell transplantation has several potential advantages over autologous transplantation for NHL,including procurement of an uncontaminated stem-cell graft, GvL effects, and the elimination of hematopoietic stem-cell damage and consequent secondary leukemia. RESULTS The ideal application of allogeneic transplantation in aggressive and high-grade lymphomas is still unclear; but the lower relapse rates demonstrated in several comparisons of the two approaches make this an exciting area to pursue. Finally, non-myeloablative stem-cell transplantation may broaden the use of allogeneic transplantation by lowering regimen-related mortality while capitalizing on GvL.

Phase II study of immunomodulation with granulocyte-macrophage colony-stimulating factor, interleukin-2, and rituximab following autologous stem cell transplant in patients with relapsed or refractory lymphomas

High-dose chemotherapy followed by autologous stem cell transplant (ASCT) leads to durable remissions in approximately half of patients with chemosensitive relapsed or refractory aggressive lymphomas; however, many will relapse despite ASCT secondary to persistent minimal residual disease (MRD) or malignant graft contamination. Post-transplant rituximab may eradicate MRD. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2) might enhance the efficacy of rituximab by augmenting antibody-dependent cellular cytotoxicity (ADCC). We hypothesized that given together, rituximab, GM-CSF, and IL-2 might eradicate MRD and improve event-free survival following ASCT. Forty-six patients with relapsed non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL) were enrolled. Stem cells were mobilized with G-CSF and GM-CSF following chemotherapy. Following BEAM conditioning, patients received GM-CSF until neutrophil engraftment. Between days + 30 and + 120, patients received one dose of rituximab 375 mg/m2 (cycle 1), followed by three cycles of GM-CSF 250  μg/m2/day SQ days 1–5, IL-2 1.5 × 106 IU/m2/day SQ days 6–12, and rituximab 375 mg/m2 IV day 9, repeated every 21 days. Thirty-eight patients were eligible for post-ASCT immunotherapy. Nine patients completed 1–2 cycles and 21 completed 3–4 cycles; eight patients did not receive post-ASCT immunotherapy. Grade 3–4 neutropenia and grade 3 thrombocytopenia were observed. With a median follow-up of 30 months, the estimated 5-year OS and EFS for all patients eligible for immunotherapy are 65% and 45%, respectively. Post-ASCT immunomodulation with rituximab, IL-2, and GM-CSF was feasible and safe, but not all patients were able to continue on to post-ASCT immunotherapy.

A Phase I dose escalation trial of continuous infusion paclitaxel to augment high dose cyclophosphamide and thiotepa plus stem cell rescue for the treatment of patients with advanced breast carcinoma

Paclitaxel, an effective chemotherapeutic agent in the management of breast carcinoma, may have activity in women whose disease has recurred after high dose chemotherapy. With this is mind the authors explored the addition of a 120‐hour continuous infusion of paclitaxel to a previously reported regimen comprised of high dose cyclophosphamide and thiotepa.

Treatment of myelodysplastic syndrome with 2 schedules and doses of oral topotecan: a randomized phase 2 trial by the Cancer and Leukemia Group B (CALGB 19803).

The Cancer and Leukemia Group B evaluated oral topotecan administered at 2 schedules and doses for myelodysplastic syndrome (MDS).

Timing of platelet recovery is associated with adequacy of leukapheresis product yield after cyclophosphamide and G-CSF in patients with lymphoma

A subgroup of patients with refractory Hodgkins (HD) or non‐Hodgkins (NHL) lymphoma may be cured with high‐dose chemotherapy and peripheral blood progenitor cell rescue. To investigate the relationship of adequate leukapheresis yield and time course of platelet recovery after mobilization chemotherapy, we retrospectively analyzed the leukapheresis yields in seven patients with Hodgkins disease and fifteen patients with non‐Hodgkins lymphoma undergoing high‐dose chemotherapy. Our goal was to develop a rule to determine when to initiate leukapheresis and then to prospectively validate this rule. All patients were mobilized with cyclophosphamide and G‐CSF (granulocyte‐colony stimulating factor). A total of 144 leukaphereses were completed and analyzed. Based on the CD34 content in the initial harvest product, fifteen patients were defined as poor mobilizers (CD34 < 0.15 × 106/kg) and seven were good mobilizers. The platelet count on the first day of harvesting was significantly associated with the poor mobilizers (P = .03). Age, sex, marrow involvement, disease (HD vs. NHL), prior radiation, time since last chemotherapy, and total number of cycles of prior chemotherapy were not predictive of poor mobilizers. By using a platelet count cut off of 35 × 109/L, we retrospectively analyzed 144 individual leukapheresis products, to test whether CD34 yield was predicted by the peripheral blood platelet count on the day of leukapheresis. This rule had an excellent sensitivity, 91%, and a specificity of 67%. Subsequently, we validated this rule with the next twenty‐four patients undergoing leukapheresis of which there were 143 leukaphereses. The prediction rule exhibited a sensitivity of 72% and a specificity of 68% in the validation set. There does appear to be utility in using the platelet count to guide the initiation of leukapheresis after chemotherapy and G‐CSF mobilization. J. Clin. Apheresis 14:31–34, 1999.© 1999 Wiley‐Liss, Inc.

Prognostic Testing Patterns and Outcomes of Chronic Lymphocytic Leukemia Patients Stratified by Fluorescence In Situ Hybridization/Cytogenetics: A Real-world Clinical Experience in the Connect CLL Registry

Introduction Prognostic genetic testing is recommended for patients with chronic lymphocytic leukemia (CLL) to guide clinical management. Specific abnormalities, such as del(17p), del(11q), and unmutated IgHV, can predict the depth and durability of the response to CLL therapy. Patients and Methods In the present analysis of the Connect CLL Registry (ClinicalTrials.gov identifier, NCT01081015), a prospective observational cohort study of patients treated across 199 centers, the patterns of prognostic testing and outcomes of patients with unfavorable‐risk genetics were analyzed. From 2010 to 2014, 1494 treated patients were enrolled in the registry by line of therapy (LOT), and stratified by the results of cytogenetic/fluorescence in situ hybridization (FISH) testing into 3 risk levels: unfavorable (presence of del[17p] or del[11q]), favorable (absence of del[17p] and del[11q]), and unknown. Results Cytogenetic/FISH testing was performed in 861 patients (58%) at enrollment; only 40% of these patients were retested before starting a subsequent LOT. Of those enrolled at the first LOT, unfavorable‐risk patients had inferior event‐free survival compared with favorable‐risk patients (hazard ratio, 1.60; P = .001). Event‐free survival was inferior with bendamustine‐containing regimens (P < .0001). Event‐free survival did not differ significantly between risk groups for patients treated with ibrutinib or idelalisib in the relapse/refractory setting. The predictors of reduced event‐free survival included unfavorable‐risk genetics, age ≥ 75 years, race, and treatment choice at enrollment. Conclusion The present study has shown that prognostic cytogenetic/FISH testing is infrequently performed and that patients with unfavorable‐risk genetics treated with immunochemotherapy combinations have worse outcomes. This underscores the importance of performing prognostic genetic testing for all CLL patients to guide treatment. Micro‐Abstract Prognostic genetic testing can guide treatment decisions and predict outcomes for patients with chronic lymphocytic leukemia (CLL). Among 1494 patients with CLL treated in the community setting, prognostic genetic testing was infrequently performed and the outcomes were inferior for patients with unfavorable‐risk disease. This highlights the importance of prognostic testing for patients with CLL to guide treatment and improve outcomes.

Phase II study of intravenous melphalan (NSC-8806) in the treatment of patients with advanced squamous carcinoma of the head and neck

The Illinois Cancer Center entered 25 patients on a phase II trial of intravenous melphalan treating patients with recurrent, metastatic or locally advanced and inoperable squamous cell carcinoma of the head and neck. All patients had bi-dimensionally measurable disease, at least a sixty day life expectancy, and adequate performance status (ECOG scale ≤2). All patients except one had received prior radiotherapy, chemotherapy or both. Melphalan dosage was 30 mg/m2 every three weeks. Twenty-four patients were evaluable for response. One patient with laryngeal carcinoma had a clinical complete response of a nodal metastasis. Four patients had stabilization of disease for one to three months. There was formidable toxicity, including neutropenia (ANC < 1000/μl 36%), and thrombocytopenia (< 50,000/μl 32%). There were no drug-related deaths. Melphalan administered intravenously does not appear to be efficacious therapy in patients with previously treated advanced head and neck squamous carcinomas.