Treatment recommendations for patients with Waldenström macroglobulinemia (WM) and related disorders: IWWM-7 consensus.

Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of International Workshops on WM (IWWM). As part of the IWWM-7 and based on recently published and ongoing clinical trials, the panels updated treatment recommendations. Therapeutic strategy in WM should be based on individual patient and disease characteristics (age, comorbidities, need for rapid disease control, candidacy for autologous transplantation, cytopenias, IgM-related complications, hyperviscosity, and neuropathy). Mature data show that rituximab combinations with cyclophosphamide/dexamethasone, bendamustine, or bortezomib/dexamethasone provided durable responses and are indicated for most patients. New monoclonal antibodies (ofatumumab), second-generation proteasome inhibitors (carfilzomib), mammalian target of rapamycin inhibitors, and Bruton's tyrosine kinase inhibitors are promising and may expand future treatment options. A different regimen is typically recommended for relapsed or refractory disease. In selected patients with relapsed disease after long-lasting remission, reuse of a prior effective regimen may be appropriate. Autologous stem cell transplantation may be considered in young patients with chemosensitive disease and in newly diagnosed patients with very-high-risk features. Active enrollment of patients with WM in clinical trials is encouraged.

Ocular adnexal MALTomas: case series of patients treated with primary radiation.

BACKGROUND: Ocular adnexal mucosal-associated lymphoid tissue lymphomas (MALTomas) are rare, and there are no phase III trials to guide treatment. Primary radiation therapy has been the typical management. This retrospective series reports the experience of a single institution and adds to the current literature. METHODS: Our electronic medical record system and available paper charts were used to identify patients with MALTomas of the lacrimal gland or sac, conjunctiva, and orbital structures, including extraocular muscles. In order to determine pathology, staging, treatment information, local and distant control, salvage treatments, and late toxicity, records were reviewed. RESULTS: Sixteen patients with ocular adnexal MALTomas had local radiation between 1992 and 2011 for primary or recurrent disease. Fifty percent of patients had lymphoma in the conjunctiva, 25% had lymphoma in the lacrimal sac/gland, and 25% of patients had lymphoma in the posterior orbit. Stage IAE disease occurred in 75% of patients, 6% had stage IIAE disease, and 19% of patients had a positive bone marrow biopsy. One patient received chemotherapy as part of initial therapy. The median radiation dose was 30 Gy (25.5-36 Gy) delivered with electrons (31%) or photons (69%). After a mean follow-up of 62.8 months, 2 patients had residual/progressive disease, 2 had contralateral recurrence, and 1 patient had a distant failure, for local control of 87.5% and overall disease control of 68.75%. Recurrence/progression occurred at a median of 35.45 months. Two patients with residual/progressive disease and 1 patient with a contralateral recurrence were followed, successfully salvaged, and have no evidence of disease. Fourteen patients are still alive, and there were no disease-related/toxicity deaths. Seven patients developed cataracts in the treated eye, 2 patients had radiation retinopathy, 2 had permanent dry eye syndrome, and 1 patient had severe keratopathy requiring enucleation. Six patients (3.75%) had worsening visual acuity of unclear etiology. CONCLUSIONS: Primary radiation therapy for ocular adnexal MALTomas with a median dose of 30 Gy led to excellent local control. Patients who did recur were successfully salvaged. Radiation was generally well tolerated, with expected cataractogenesis, given the dose required to achieve local control (with only 1 patient developing severe keratopathy after receiving the highest dose in this series).

Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia.

Certain malignant B cells rely on B-cell receptor (BCR)-mediated survival signals. Spleen tyrosine kinase (Syk) initiates and amplifies the BCR signal. In in vivo analyses of B-cell lymphoma cell lines and primary tumors, Syk inhibition induces apoptosis. These data prompted a phase 1/2 clinical trial of fostamatinib disodium, the first clinically available oral Syk inhibitor, in patients with recurrent B-cell non-Hodgkin lymphoma (B-NHL). Dose-limiting toxicity in the phase 1 portion was neutropenia, diarrhea, and thrombocytopenia, and 200 mg twice daily was chosen for phase 2 testing. Sixty-eight patients with recurrent B-NHL were then enrolled in 3 cohorts: (1) diffuse large B-cell lymphoma (DLBCL), (2) follicular lymphoma (FL), and (3) other NHL, including mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma, lymphoplasmacytic lymphomas, and small lymphocytic leukemia/chronic lymphocytic leukemia (SLL/CLL). Common toxicities included diarrhea, fatigue, cytopenias, hypertension, and nausea. Objective response rates were 22% (5 of 23) for DLBCL, 10% (2 of 21) for FL, 55% (6 of 11) for SLL/CLL, and 11% (1/9) for MCL. Median progression-free survival was 4.2 months. Disrupting BCR-induced signaling by inhibiting Syk represents a novel and active therapeutic approach for NHL and SLL/CLL. This trial was registered at www.clinicaltrials.gov as #NCT00446095.

Long-term outcomes to fludarabine and rituximab in Waldenström macroglobulinemia.

We report the long-term outcome of a multicenter, prospective study examining fludarabine and rituximab in Waldenström macroglobulinemia (WM). WM patients with less than 2 prior therapies were eligible. Intended therapy consisted of 6 cycles (25 mg/m(2) per day for 5 days) of fludarabine and 8 infusions (375 mg/m(2) per week) of rituximab. A total of 43 patients were enrolled. Responses were: complete response (n = 2), very good partial response (n = 14), partial response (n = 21), and minor response (n = 4), for overall and major response rates of 95.3% and 86.0%, respectively. Median time to progression for all patients was 51.2 months and was longer for untreated patients (P = .017) and those achieving at least a very good partial response (P = .049). Grade 3 or higher toxicities included neutropenia (n = 27), thrombocytopenia (n = 7), and pneumonia (n = 6), including 2 patients who died of non-Pneumocystis carinii pneumonia. With a median follow-up of 40.3 months, we observed 3 cases of transformation to aggressive lymphoma and 3 cases of myelodysplastic syndrome/acute myeloid leukemia. The results of this study demonstrate that fludarabine and rituximab are highly active in WM, although short- and long-term toxicities need to be carefully weighed against other available treatment options. This study is registered at clinicaltrials.gov as NCT00020800.

Clinical and laboratory features of myelofibrosis and limitations of current therapies.

Myelofibrosis (MF) is a life-threatening clonal stem cell malignancy characterized by progressive bone marrow fibrosis and ineffective hematopoiesis. The term "MF" encompasses primary myelofibrosis (PMF) as well as 2 other phenotypically similar malignancies: post-polycythemia vera (PV) MF (PPV-MF) and post-essential thrombocythemia (ET) MF (PET-MF). The World Health Organization classification system for myeloid malignancies recognizes PMF, PV, ET, and chronic myeloid leukemia (CML) as the "classic" myeloproliferative neoplasms (MPNs). Patients with low- or intermediate-1-risk disease have a median survival of 6-15 years, in contrast to those with intermediate-2- or high-risk disease, which is associated with a considerably worse prognosis. Following transformation into (secondary) acute myeloid leukemia (AML), the prognosis of MF is even worse, with a median survival of 3 months or less. Due to the heterogeneous nature of MF, the diagnosis and treatment of this malignancy can be challenging. At present, the only treatment that can be applied with curative intent is allogeneic stem cell transplantation (SCT), whereas no other specific therapies exist that are approved by the US Food and Drug Administration (FDA) for MF. Since most patients with MF appear not to be eligible for allogeneic SCT, patients are often treated by conventional "older" drugs such as androgens and hydroxyurea (HU; hydroxycarbamide), with the principal objective being palliation. Following the establishment of a causal role of a specific mutation in the Janus kinase type 2 (JAK2) gene, namely JAK2V617F, in the molecular pathogenesis of MPNs in 2005, many efforts have been directed towards the development of novel JAK2 (including JAK1/JAK2) inhibitors. Other investigative approaches include immunomodulatory agents, histone deacetylase inhibitors, hedgehog inhibitors, and others. Recently, the positive results of the first in class of the JAK1/JAK2 inhibitors, ruxolitinib (formerly INCB18242), from 2 large phase III studies were presented and are discussed herein.

Harnessing the energy: development of radioimmunotherapy for patients with non-Hodgkin's lymphoma.

Radioimmunotherapy (RIT) combines the use of targeted monoclonal antibodies with radionuclides for the treatment of non-Hodgkin's lymphoma (NHL), taking advantage of its inherent radiosensitivity. A number of trials have shown significantly higher response rates and longer progression-free survival times in patients treated with the CD20-targeted radioimmunoconjugate yttrium-90-ibritumomab tiuxetan compared with the standard of care. Furthermore, these benefits have also been shown in heavily pretreated patients who relapsed or were resistant to rituximab. Currently, a number of different treatment regimens and strategies are available for the treatment of NHL patients. Therefore, in an attempt to minimize toxicity, maximize efficacy, and improve survival, it is crucial to appropriately select patients who are good candidates for individual treatment approaches. A strategy for patient selection has been developed, including the use of existing patient assessment tools, such as the Follicular Lymphoma International Prognostic Index, to determine the optimal regimen for patients with follicular lymphoma according to their disease characteristics and physical condition. Patients who are fit make ideal candidates for potentially curative regimens, which include induction chemotherapy with or without immunotherapy followed by RIT consolidation and, potentially, maintenance therapy. Patients who are considered "compromised" would also benefit from induction treatment and RIT consolidation, with a view to reducing the lymphoma burden and decreasing the risk for disease progression. "Frail" patients would be better suited to supportive therapy to control symptoms. This paper explores factors that should be considered when assessing whether a patient is a good candidate for treatment with RIT, and aids physicians in the selection of the most appropriate therapy for each patient group.

Mesenchymal stem cells from the Wharton's jelly of umbilical cord segments provide stromal support for the maintenance of cord blood hematopoietic stem cells during long-term ex vivo culture.

BACKGROUND: Hematopoietic stem cells (HSCs) are routinely obtained from marrow, mobilized peripheral blood, and umbilical cord blood. Mesenchymal stem cells (MSCs) are traditionally isolated from marrow. Bone marrow-derived MSCs (BM-MSCs) have previously demonstrated their ability to act as a feeder layer in support of ex vivo cord blood expansion. However, the use of BM-MSCs to support the growth, differentiation, and engraftment of cord blood may not be ideal for transplant purposes. Therefore, the potential of MSCs from a novel source, the Wharton's jelly of umbilical cords, to act as stromal support for the long-term culture of cord blood HSC was evaluated. STUDY DESIGN AND METHODS: Umbilical cord-derived MSCs (UC-MSCs) were cultured from the Wharton's jelly of umbilical cord segments. The UC-MSCs were then profiled for expression of 12 cell surface receptors and tested for their ability to support cord blood HSCs in a long-term culture-initiating cell (LTC-IC) assay. RESULTS: Upon culture, UC-MSCs express a defined set of cell surface markers (CD29, CD44, CD73, CD90, CD105, CD166, and HLA-A) and lack other markers (CD45, CD34, CD38, CD117, and HLA-DR) similar to BM-MSCs. Like BM-MSCs, UC-MSCs effectively support the growth of CD34+ cord blood cells in LTC-IC assays. CONCLUSION: These data suggest the potential therapeutic application of Wharton's jelly-derived UC-MSCs to provide stromal support structure for the long-term culture of cord blood HSCs as well as the possibility of cotransplantation of genetically identical, HLA-matched, or unmatched cord blood HSCs and UC-MSCs in the setting of HSC transplantation.

Phase I trial of toll-like receptor 9 agonist PF-3512676 with and following rituximab in patients with recurrent indolent and aggressive non Hodgkin's lymphoma.

PURPOSE: PF-3512676 (formerly CpG 7909) is a novel Toll-like receptor 9-activating oligonucleotide with single-agent antitumor activity that augments preclinical rituximab efficacy. This Phase I trial was designed to investigate the safety, tolerability, and preliminary antitumor activity of PF-3512676 in combination with rituximab. EXPERIMENTAL DESIGN: Patients with relapsed/refractory CD20+ B cell non-Hodgkin's lymphoma received i.v. rituximab (375 mg/m2/week for 4 weeks) and PF-3512676 weekly for 4 weeks either i.v. (0.04, 0.16, 0.32, or 0.48 mg/kg) or s.c. (0.01, 0.04, 0.08, or 0.16 mg/kg). An additional extended-treatment cohort received 4 weeks of 0.24 mg/kg s.c. PF-3512676 in combination with rituximab followed by s.c. PF-3512676 alone weekly for 20 weeks. RESULTS: Patients (N = 50) had received a median of three prior therapies (range, 1-11) including rituximab in 80% of patients. Treatment-related adverse events occurred in 11 of 19 (58%) i.v. patients, 15 of 19 (79%) s.c. patients, and all 12 patients in the extended-treatment cohort. Most common adverse events were mild to moderate systemic flu-like symptoms and injection-site reactions (s.c. cohorts only). Grade 3/4 neutropenia occurred in four patients. Objective responses occurred in 12 of 50 (24%) patients overall and in 6 of 12 (50%) patients in the extended-treatment cohort, including 2 patients with rituximab-refractory disease. CONCLUSION: Brief or extended-duration PF-3512676 can be safely administered in combination with rituximab in patients with relapsed/refractory non-Hodgkin's lymphoma.

Optimizing the treatment of patients with rituximab-pretreated recurrent indolent non-Hodgkin lymphoma.

Indolent non-Hodgkin lymphomas (NHLs) are among the most prevalent hematologic malignancies; their incidence has been increasing over the last several decades. Because advanced-stage indolent lymphoma is generally incurable, therapy for this group of patients is geared toward chronic management over years. Recently, numerous trials have demonstrated that the combination of chemotherapy and the anti-CD20 monoclonal antibody rituximab can provide superior efficacy to chemotherapy alone. Thus, rituximab-containing regimens are the standard approach for primary therapy in patients with symptomatic advanced disease. As these patients progress and receive multiple rituximab-based regimens over time, new treatment options are needed for this new group of rituximab-pretreated patients. This review focuses on the development of novel therapies for rituximab-pretreated, relapsed or refractory indolent NHL.

A phase II multicenter study of troxacitabine in relapsed or refractory lymphoproliferative neoplasms or multiple myeloma.

Options for patients with relapsed/refractory lymphoproliferative disorders and multiple myeloma are currently limited. Troxacitabine has shown promise in preclinical studies in a variety of malignancies; hence, the current study was conducted to evaluate the activity of troxacitabine in relapsed or refractory lymphoid malignancies. This was a phase II, open-label, multinational, multicenter study of patients with relapsed or refractory lymphoproliferative disorders or multiple myeloma. Thirty-four adults were enrolled in the study and received the study drug at either 5.4 mg/m2 (n = 16) or 4.3 mg/m2 (n = 18). The dose was decided in a phase I study, during which dose escalation was carried to reach a maximum tolerated dose with an acceptable toxicity profile. Two separate phase I studies were performed in Europe and the US. Troxacitabine was administered by intravenous infusion over 30 min daily for days 1 - 5 every 4 weeks. Treatment was continued to disease progression or until the subjects met criteria for withdrawal or unacceptable toxicities were evident as outlined in the protocol. Two patients had a partial response (PR) to treatment with troxacitabine to yield an overall response rate of 13%. There were no complete responses seen with the drug. Stable disease was achieved in 15 patients (44%). All patients had at least one treatment related adverse event, which led to six withdrawals from the study. Hematologic toxicity constituted the most common adverse events. Serious adverse effects were seen in 62% of patients. None of the 13 deaths were attributed directly to troxacitabine. As a single agent, troxacitabine has limited benefit in patients with advanced lymphoproliferative disorders or multiple myeloma. Future studies will be needed to address modified dosing according to emerging pharmacokinetic and pharmacodynamic data and combination therapy which may lead to improved clinical benefit for troxacitabine in hematologic malignancies.

Efficacy and safety of rituximab combined with ESHAP chemotherapy for the treatment of relapsed/refractory aggressive B-cell non-Hodgkin lymphoma.

BACKGROUND: We evaluated the efficacy and safety of adding rituximab to nonanthracycline ESHAP (etoposide/methylprednisolone/cytarabine/cisplatin) chemotherapy for relapsed/refractory aggressive non-Hodgkin lymphoma (NHL). PATIENTS AND METHODS: Patients with intermediate- or high-grade NHL were to receive 6 rituximab doses and 6 ESHAP cycles. Rituximab 375 mg/m(2) was administered 1 week and 1 day before cycle 1 of standard ESHAP (etoposide 40 mg/m(2) on days 1-4; methylprednisolone 500 mg/m(2) on days 1-5; cytarabine 200 mg/m(2) on day 5; and cisplatin 25 mg/m(2) on days 1-4). Rituximab was repeated before the third and fifth 21-day ESHAP cycles (on days 48 and 90 of protocol, respectively), followed by 2 additional rituximab doses after cycle 6 (on days 134 and 141 of protocol). Use of growth factors was permitted. Thirteen patients were enrolled (median age, 56 years); all had previously treated NHL, 12 (92%) had diffuse large B-cell lymphoma, 10 (77%) had stage III/IV disease, and 2 (15%) had chemotherapy-refractory disease. RESULTS: The most common grade 3/4 toxicities were neutropenia and thrombocytopenia, with 3 cases of febrile neutropenia. Seven patients exhibited complete response (CR) and 3 had partial response, for an objective response rate of 77%. Median duration of response for all responders was 14 months (range, 2-51 months). Among 6 patients completing all 6 cycles, 4 (67%) had a CR, 1 had a partial response, and 1 had progressive disease. Three of the 4 CRs have remained for a median of 48 months (range, 46-51 months). CONCLUSION: Rituximab plus ESHAP led to durable responses with acceptable toxicity in patients with relapsed/refractory aggressive NHL, most of whom had advanced disease.

Emerging treatments for indolent lymphoma.

Non-Hodgkin lymphomas (NHLs) comprise a diverse group of lymphatic malignancies of primarily B-cell origin, which are steadily increasing in prevalence worldwide. Approximately 63,190 new cases of NHL are expected to be diagnosed in the United States in 2007, representing 4% of all cancers. Further, the annual incidence rate of NHL in 2000-2004, estimated from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute, was 19.3 cases per 100,000 persons. Of these, the indolent NHLs, although initially responsive to a variety of therapeutic regimens, have a continuous relapsing nature and are essentially incurable. Over the past decade, the availability of monoclonal antibodies has revolutionized the treatment of patients with various types of NHL. To date, the most noteworthy agent of this type has been rituximab, an antibody directed against the CD20 antigen found on the majority of B-cell lymphomas. Rituximab is associated with improved and durable responses as a single agent and in combination with chemotherapy for patients with newly diagnosed or relapsed/refractory NHL. Recent data suggest an improvement in survival in recently diagnosed patients who have had access to rituximab therapy and provide new insights into the use of rituximab in frontline combination chemotherapy and as maintenance therapy. Other emerging therapeutics include new chemotherapeutics, small-molecule and monoclonal antibodies, radioimmunotherapy, apoptosis-inducing agents, and immunomodulators.

Phase 2 study of CHOP-R-14 followed by 90Y-ibritumomab tiuxetan in patients with previously untreated diffuse large B-cell lymphoma.

The aim of this open-label, single-center, phase 2 study was to assess the efficacy and safety of dose-dense CHOP-R-14 followed by 90Y-ibritumomab radioimmunotherapy (RIT) in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). A total of 20 patients, the majority presenting with high-risk characteristics, were enrolled to receive dose-dense cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab every 14 days (CHOP-R-14), followed by 90Y-ibritumomab tiuxetan consolidation. Sixteen patients completed RIT consolidation (rituximab 250 mg/m2 on day 1 and day 7, 8, or 9, followed by a single injection of 90Y-ibritumomab). Complete response (CR) rates of 75 and 95% were observed after treatment with CHOP-R-14 and RIT, respectively; 4 of the 5 patients who achieved a partial response after CHOP-R-14 converted to CR following treatment with RIT. With a median follow-up of 89.7 months, the progression-free and overall survival rates for the cohort were 75 and 85%, respectively. Hematological adverse events were common following CHOP-R-14 and RIT, but they were manageable with treatment interruption. Therefore, this regimen achieved promising survival outcomes in high-risk DLBCL on long term follow-up, with manageable toxicity.

Re-treatment with I-131 tositumomab in patients with non-Hodgkin's lymphoma who had previously responded to I-131 tositumomab.

PURPOSE: To study efficacy and safety of re-treatment with I-131 tositumomab in patients with low-grade, follicular, or transformed low-grade B-cell lymphoma who relapsed following a response to I-131 tositumomab. PATIENTS AND METHODS: A prior response > or = 3 months to I-131 tositumomab was required. The single therapeutic dose following a dosimetric dose was adjusted to give the same total body dose (in Gy) as that used for the original dose, or was attenuated if the platelet count was less than 150,000 per mm(3) or if the prior treatment resulted in grade 4 cytopenias lasting longer than 7 days. RESULTS: Of 32 patients enrolled, 28 completed the therapeutic dose. A median of four therapies were given before re-treatment. Eighteen (56%) of 32 patients had a complete or partial response (median duration, 15.2 months); eight (25%) had a complete response (median duration, 35 months). Five continue in response from 1.8 to 5.7 years, with a median follow-up of 35 months. The overall median response duration was not significantly different for the two treatments, with no clinical factors predicting response or its duration. Ten of 18 re-responders had longer responses with re-treatment, with five having responses > or = 1.5 years longer. Grade 3/4 neutropenia and thrombocytopenia occurred in 50% and 43% of patients, respectively, similar to initial treatment. Antimouse antibodies developed in 10% of patients, and 12% developed elevated serum thyroid-stimulating hormone. Six patients were diagnosed with second malignancies, including four patients who developed myelodysplastic syndrome (one who had not received the therapeutic dose) and one with acute myelogenous leukemia. CONCLUSION: Re-treatment with I-131 tositumomab following a previous response can produce second responses that can be durable.

CHOP Chemotherapy Followed by Tositumomab and Iodine-131 Tositumomab for Previously Untreated Diffuse Large B-cell Lymphoma.

The efficacy and safety of tositumomab/iodine-131 tositumomab (TST/I-131 TST) were evaluated in diffuse large B-cell lymphoma patients who responded to first-line cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Fifteen patients (median age, 52 years) received dosimetric and therapeutic doses of TST/I-131 TST. The most common Grade 3/4 hematologic adverse events were decreased absolute neutrophil count (47%), white blood cell count (40%), platelet count (27%), and hemoglobin (20%). The complete response (CR) rate increased from 60% post-CHOP to 80% post TST / I-131 TST. With a median follow-up of 120.0 months (range, 14-130 months), median duration of response (95% confidence intervals) was 58.4 months (12.0-not reached [NR]) for patients with confirmed complete response and 58.4 months (20.9-NR) for all confirmed responders. Median progression-free survival and time to treatment failure were 63.0 months (16.1-NR). Median overall survival was not reached; 2 patients died on study. CHOP and TST/I-131 TST demonstrated clinical activity with acceptable toxicity.

The combination of fludarabine, cyclophosphamide, and granulocyte-macrophage colony-stimulating factor in the treatment of patients with relapsed chronic lymphocytic leukemia and low-grade Non-Hodgkin's lymphoma.

PURPOSE: The goal of this study was to evaluate the efficacy of the fludarabine/cyclophosphamide combination in patients with relapsed chronic lymphocytic lymphoma (CLL) and low-grade non-Hodgkin's lymphoma (NHL) and to assess the impact of adding granulocyte-macrophage colony-stimulating factor (GM-CSF) to this regimen in a randomized fashion. PATIENTS AND METHODS: Thirty-four patients (CLL, n=16; low-grade NHL, n=18) were enrolled. The median number of previous treatments was 2. Patients received 6 months of previous therapy with an alkylating agent or had preexisting cytopenias received a 25% dose reduction. Twenty-two patients (65%) were randomized to receive GM-CSF. Patients completed a median of 5 cycles of treatment (range, 1-6 cycles). Twenty-seven patients (80%) received >or=3 cycles of treatment and were evaluated for response. RESULTS: Seven patients (26%) exhibited a complete response; 6 of the 7 had low-grade NHL. Fourteen patients (52%) exhibited a partial response, and 6 patients (22%) had stable disease. Notably, 6 of the 7 patients who exhibited complete response and 9 of 14 patients with partial responses were randomized to the GM-CSF arm. The duration of response ranged from 4 months to 26 months. The toxicities were mainly hematologic. Nineteen patients (70%) experienced >or=1 episode of grade 3/4 neutropenia, but only 4 (15%) experienced febrile neutropenia; 3 of those patients were assigned to the GM-CSF arm. CONCLUSIONS: The combination of fludarabine and cyclophosphamide is a well-tolerated and effective treatment regimen for patients with relapsed CLL and low-grade NHL. A higher percentage of complete responses were noted in patients with low-grade NHL compared with patients with CLL. Granulocyte-macrophage colony-stimulating factor did not seem to decrease the incidence of febrile neutropenia. However, the higher number of complete and partial responses noted on the GM-CSF arm is intriguing and warrants further investigation.