Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia

The best initial therapy for elderly patients with chronic lymphocytic leukemia (CLL) has not yet been defined. We investigated the activity of lenalidomide as initial therapy for elderly patients with CLL. Sixty patients with CLL 65 years of age and older received treatment with lenalidomide orally 5 mg daily for 56 days, then titrated up to 25 mg/d as tolerated. Treatment was continued until disease progression. At a median follow-up of 29 months, 53 patients (88%) are alive and 32 patients (53%) remain on therapy. Estimated 2-year progression-free survival is 60%. The overall response rate to lenalidomide therapy is 65%, including 10% complete response, 5% complete response with residual cytopenia, 7% nodular partial response, and 43% partial response. Neutropenia is the most common grade 3 or 4 treatment-related toxicity observed in 34% of treatment cycles. Major infections or neutropenic fever occurred in 13% of patients. Compared with baseline levels, we noted an increase in serum immunoglobulin levels across all classes, and a reduction in CCL3 and CCL4 plasma levels was noted in responding patients. Lenalidomide therapy was well tolerated and induced durable remissions in this population of elderly, symptomatic patients with CLL. This study was registered at www.clinicaltrials.gov as #NCT00535873.     

Optimal initial therapy for patients with newly diagnosed chronic myeloid leukemia in chronic phase

PURPOSE OF REVIEW: Imatinib mesylate, a tyrosine kinase inhibitor, has revolutionized the therapy of newly diagnosed patients with chronic myeloid leukemia. Prior to imatinib, treatment algorithms for chronic myeloid leukemia patients recommended stem cell transplantation for patients less than 50 years old who had a donor and could undergo stem cell transplantation. Other than stem cell transplantation, interferon was the only drug that could induce cytogenetic remissions in minority of patients. RECENT FINDINGS: After 5 years of follow-up, the rate of relapse with imatinib therapy continues to decrease, and the numbers of patients achieving a complete molecular response continue to increase. In addition, with a longer follow up, imatinib continues to be safe and easily tolerated. Recent studies have shown a survival benefit with imatinib. The use of imatinib before stem cell transplant did not have an effect on mortality or morbidity posttransplant. SUMMARY: Currently, imatinib is considered first line therapy in all patients with early chronic phase chronic myeloid leukemia with stem cell transplant reserved for patients who have disease resistant to imatinib therapy. Our aim is to review current recommendations for initial therapy of patients with early chronic phasechronic myeloid leukemia, current areas of controversy and future directions.     

Treatment options for newly diagnosed patients with chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is an indolent B-cell malignancy for which early intervention has not been shown to extend survival. However, there are many agents available that are active in this disease. Alkylating agents, the purine analogs, and monoclonal antibodies have all been shown to result in high response rates in patients with previously treated and untreated CLL. These classes of agents have been combined based on in vitro data demonstrating synergism. The purine analogs alone or in combination with alkylating agents and monoclonal antibodies result in greater response rates compared with alkylating agent-based therapy alone. However, improvement in overall survival and cure of patients with CLL has yet to be realized with these available regimens. The best initial therapy of patients with CLL remains a matter of debate.     

Interferon maintenance therapy for patients with chronic lymphocytic leukemia in remission after fludarabine therapy

Many patients with chronic lymphocytic leukemia (CLL) achieve remission after treatment with fludarabine chemotherapy. Most of these patients, however, later experience relapse. In addition, immunologic deficits may persist even in patients in complete remission; lymphopenia, predominantly involving the CD4 population, is universal after fludarabine therapy. We used recombinant alpha interferon (IFN-alpha) maintenance therapy in patients with CLL who achieved remission in response to fludarabine therapy to determine its effect on residual disease, assessed by either bone marrow biopsy or flow cytometry, and on immune restoration. Thirty-one patients were treated with IFN-alpha (3 x 10(6) U by subcutaneous injection three times weekly). Twenty-two patients (71%) were in complete remission (CR) and nine (29%) were in partial remission (PR). Of the 22 patients in CR, 21 (95%) had evidence of residual disease at the start of IFN-alpha therapy. Low CD4 levels were noted in 93% of patients, low IgG levels in 45%, and anergy or hypoergy in 52%. Only one patient in PR achieved a CR on IFN-alpha therapy: the only patient who had had no prior fludarabine but had been treated with chlorambucil and prednisone. All patients in CR with minimal residual disease had persistent disease after IFN-alpha treatment. There were no increases in CD4 counts or IgG levels; three patients with borderline responses to skin testing had an increase in the number of positive tests while on IFN-alpha. The time to progression was no different in patients treated with IFN-alpha than in a historical control group of patients who had received no further therapy after fludarabine. In summary, the use of IFN-alpha maintenance did not eradicate residual disease, restore immune function, or prolong remissions in patients with CLL responsive to fludarabine.     

Alpha-interferon as maintenance drug after initial fludarabine therapy for patients with chronic lymphocytic leukemia and low-grade non-Hodgkin's lymphoma

BACKGROUND: Fludarabine monophosphate (FLU) is an adenine nucleoside analogue with promising therapeutic activity in lymphoproliferative disorders. In addition, the effectiveness of alpha-interferon (alpha-IFN) in low-grade non-Hodgkin's lymphoma (LG-NHL) and B-cell chronic lymphocytic leukemia (B-CLL) has been demonstrated in several clinical trials. METHODS: In a phase II study of 45 patients with B-CLL and 28 with LG-NHL, we used FLU as second and third-line chemotherapy. Dosages of 25 mg/m2 were given in 30-minute infusions for 5 consecutive days. Treatment was repeated every 28 days depending on patients' clinical status for a maximum of 6 cycles. Entrance in the human lymphoblastoid alpha-IFN maintenance portion of the study depended on response to initial FLU. Following randomization we administered alpha-IFN, or no therapy at all, to patients who obtained a complete or a partial response after FLU therapy. The alpha-IFN dose was 3 x 10(6) U three times per week until disease progression. RESULTS: Twenty-one B-CLL patients achieved major responses, as did 17 of those with LG-NHL. Twenty-four of the former group and 11 of the latter failed to respond or obtained only a minor response. The 38 patients who responded well and entered the second part of the trial showed significant prolongation of remission duration with maintenance alpha-IFN. CONCLUSIONS: In consideration of its significant activity, the role of FLU in the management of lymphoproliferative disorders needs to be evaluated further; at the same time, this preliminary analysis seems to indicate that maintenance alpha-IFN may extend remission duration in B-CLL and LG-NHL.     

Rituximab therapy of patients with B-cell chronic lymphocytic leukemia

Rituximab (IDEC-C2B8) is a chimeric antibody that binds to the B-cell surface antigen CD20. Rituximab has significant activity in follicular non-Hodgkin lymphomas. Much less is known about the effects in chronic lymphocytic leukemia (CLL). We have initiated a phase II trial to evaluate the efficacy and safety of rituximab in patients with CD20+ pretreated CLL. To avoid the rituximab-associated toxicity, we restricted the tumor cell load, as measured by the number of circulating lymphocytes and the spleen size, in the first 2 cohorts of patients included in the study. Patients received 4 intravenous infusions of 375 mg/m2 once a week over a period of 1 month. Of the 28 patients evaluable for response, 7 patients showed a partial remission (National Cancer Institute criteria) lasting for a median of 20 weeks, with 1 patient still in remission after 71 weeks. Based on lymphocyte counts only, we found at least a 50% reduction of lymphocyte counts lasting for at least 4 weeks in 13 (45%) of 29 patients. Fifteen patients from 3 institutions were monitored for the immunophenotype profile of lymphocyte subsets. The number of CD5+CD20+ cells decreased significantly and remained low until day 28 after therapy. T-cell counts were not affected. With the exception of one rituximab-related death, adverse events in the remaining patients were mild. The results suggest that rituximab has clinical activity in pretreated patients with B-CLL. Toxicity is tolerable. Response duration after withdrawal of rituximab is rather short. Therefore, other modes of application and the combination with other agents need to be tested.     

Narrative review: initial management of newly diagnosed, early-stage chronic lymphocytic leukemia

Chronic lymphocytic leukemia is one of the most common malignant lymphoid diseases in the western world and is frequently diagnosed by internists. There have been clinically significant changes in method of diagnosis, prognostic tools, supportive care, and treatment over the past 2 decades. Most patients with chronic lymphocytic leukemia now have Rai stage 0 or I disease at diagnosis. Patients with early-stage disease are a heterogeneous group: Approximately 30% to 50% will have accelerated disease progression, and the remainder may live for decades and possibly never require therapy. Recent insights into the biological characteristics of leukemic B cells have led to the discovery of new prognostic tools (immunoglobulin variable-region heavy chain gene mutation status, cytogenetic abnormalities assessed by fluorescent in situ hybridization, and Z-chain-associated protein kinase-70 protein expression) that can identify patients with early-stage disease who are at high risk for early disease progression. These tools allow physicians to individualize counseling, follow-up, and management on the basis of disease risk. In addition, new treatments developed over the past 2 decades (purine nucleoside analogues, monoclonal antibodies, and combination chemoimmunotherapy regimens) have dramatically improved response rates and appear to prolong survival. In this review, the authors discuss the current work-up of lymphocytosis and highlight how to use recently identified prognostic tools to stratify risk in patients with newly diagnosed, early-stage chronic lymphocytic leukemia. Recommendations for patient counseling, follow-up, supportive care, and initial treatment are presented for each risk category.     

Effects of monoclonal antibody therapy in patients with chronic lymphocytic leukemia

A phase I clinical trial was initiated to treat patients with stage IV B-derived chronic lymphocytic leukemia (CLL) with the IgG2a murine monoclonal antibody T101. This antibody binds to a 65,000-mol wt (T65) antigen found on normal T lymphocytes, malignant T lymphocytes, and B- derived CLL cells. All of the patients had a histologically confirmed diagnosis of advanced B-derived CLL and were refractory to standard therapy, and more than 50% of their leukemia cells reacted with the T101 antibody in vitro. The patients received T101 antibody two times per week, over two to 50 hours by intravenous administration in 100 mL of normal saline containing 5% human albumin. Twelve patients were treated with a fixed dosage of 1, 10, 50, or 100 mg, and one patient was treated with 140 mg of antibody. It was demonstrated that patients given two-hour infusions of 50 mg developed pulmonary toxicity, with shortness of breath and chest tightness. This toxicity was eliminated when infusions of 50 or 100 mg of T101 were prolonged to 50 hours. All dose levels caused a rapid but transient decrease in circulating leukemia cell counts. In vivo binding to circulating and bone marrow leukemia cells was demonstrated at all dose levels with increased binding at higher dosages. Antimurine antibody responses were not demonstrated in any patients at any time during treatment. Circulating free murine antibody was demonstrated in the serum of only the two patients treated with 100 mg of antibody as a 50-hour infusion and the patient treated with 140 mg of antibody over 30 hours. Antigenic modulation was demonstrated in patients treated at all dose levels but was particularly apparent in patients treated with prolonged infusions of 50 and 100 mg of antibody. We were also able to demonstrate antigenic modulation in lymph node cells, which strongly suggests in vivo labeling of these cells. Overall, T101 antibody alone appears to have a very limited therapeutic value for patients with CLL. The observations of in vivo labeling of tumor cells, antigenic modulation, antibody pharmacokinetics, toxicity, and antimurine antibody formation may be used in the future for more effective therapy when drugs or toxins are conjugated to the antibody.     

Murine monoclonal antibody therapy in two patients with chronic lymphocytic leukemia

We infused the murine monoclonal antibody T101 into two patients with advanced refractory chronic lymphocytic leukemia (CLL) after confirming its reactivity with their CLL cells. One patient received doses of 1, 3, and 12 mg; the second patient received 10 mg. Antibody was delivered over 10--15 min. The major observations were: (1) T101 murine monoclonal antibody did bind to cells with T65 surface antigen and saturated these cells in vivo; (2) cells that bound T101 disappeared from the circulation by 2 hr after treatment, as evidenced by a marked drop in lymphocyte counts; (3) T101 serotherapy resulted in some intravascular cell injury associated with sequestration and probably destruction in the liver and lung; (4) free serum T101 was demonstrable, but disappeared by 2--4 hr after infusion; (5) rapid infusion of T101 did not induce significant modulation of T65; (6) rapid infusion of greater than 10 mg of T101 was associated with significant systemic reactions. Monoclonal antibodies may someday have an application in leukemia therapy, but additional experimental trials are clearly indicated.     

Chronic lymphocytic leukemia diagnosed after corticosteroid therapy for Evans syndrome]

A 59-year-old woman was admitted in February 1991, because of abdominal distension. On admission, she had splenomegaly, autoimmune hemolytic anemia, and idiopathic thrombocytopenic purpura. Evans syndrome had been diagnosed and daily prednisolone therapy had been performed. After this therapy, a rapid increase of lymphocytes was observed accompanied with contraction of spleen. The monoclonal proliferation of B-lymphocytes and rearrangement of JH and J kappa gene were detected and chronic lymphocytic leukemia was diagnosed. With reduction of prednisolone, the lymphocyte counts decreased and the size of the spleen returned to the previous state. It is suspected that the cause of rapid lymphocytosis in this case was due to the redistribution of lymphocytes from the spleen to the peripheral blood.     

Analysis of CLLU1 expression levels before and after therapy in patients with chronic lymphocytic leukemia

Objective: Chronic lymphocytic leukemia (CLL) is incurable, but therapy leading to eradication of minimal residual disease (MRD) in CLL is associated with improved clinical outcomes. CLL upregulated gene 1 (CLLU1) is solely upregulated in CLL patient samples. We hypothesized that CLLU1 could be used to monitor for residual disease in CLL patient samples after therapy. Methods: We examined whether the CLLU1 real‐time quantitative PCR (RQ‐PCR) could detect small numbers of CLL cells in mixtures of normal peripheral blood mononuclear (PBMC) cells. We then performed a retrospective analysis on time‐matched cryo‐preserved specimens from patients who achieved MRD‐negative remissions that underwent serial marrow biopsies for evaluation of residual disease by 4‐color flow cytometry. RNA from PBMC samples collected at the time of the marrow assessments was analyzed for CLLU1. Nine patients underwent a total of 46 paired blood and marrow evaluations (median 5 assessments per patient). Results: CLLU1 RQ‐PCR on PBMCs of healthy donors reconstituted with varying amounts of CLL cells demonstrated leukemia cells could be reliably detected with high sensitivities depending on the CLLU1 expression level. Analysis of time‐matched samples assessed for CLLU1 levels in the blood by RQ‐PCR and residual disease of the marrow determined by 4‐color flow cytometry revealed a correlation coefficient of 0.96 (P < 0.0001). Conclusion: The CLLU1 RQ‐PCR is a sensitive and specific assay for detecting residual CLL cells after therapy. Assessment of blood CLLU1 levels can be used as a reliable marker of tumor burden and has the potential to complement currently used techniques for MRD monitoring in patients with CLL.     

A pilot study of low-dose subcutaneous alemtuzumab therapy for patients with hemotherapy-refractory chronic lymphocytic leukemia

Subcutaneous low-dose alemtuzumab (10 mg t.i.w. for 18 weeks) induced a 50% response rate, including 25% complete response, in 16 patients with refractory chronic lymphocytic leukemia (CLL) patients. The responses were substantial even in patients with unfavorable cytogenetics, fludarabine/rituximab refractoriness, Rai stage IV, previous infections, and age over 65 years. Subcutaneous low-dose alemtuzumab is effective in poor prognosis B-CLL, and has a particularly favourable toxicity profile.     

Long-term follow-up after fludarabine treatment in pretreated patients with chronic lymphocytic leukemia

BACKGROUND AND OBJECTIVES: A study update to assess long-term survival following fludarabine salvage treatment in previously treated patients with chronic lymphocytic lymphoma (CLL). DESIGN AND METHODS: From September 1992 to December 1995, 74 patients with advanced, relapsing B-cell CLL were enrolled in the study. Fludarabine was given for 5 consecutive days at the dose of 25 mg/m2/day in a 30 min infusion. Treatment was repeated every 28 days for a maximum of 6 courses.E RESULTS. Nineteen (26%) patients achieved a complete response (CR) and 20 (27%) patients had a partial response (PR), giving an overall response rate of 53%. The median overall survival was 68 months, and there was a strong negative correlation with the number of previous treatments. The median time to progression was 18 months for patients who achieved a CR and 12 months for those with a PR. INTERPRETATION AND CONCLUSIONS: The results obtained with fludarabine alone in this subset of CLL patients indicate the existence of a conspicuous disease-free survival period. This time window could be used to consolidate the initial response with either biological approaches or high-dose therapeutic strategies such as autologous bone marrow transplantation, with the aim of eventual eradication of the disease.     

Alemtuzumab in chronic lymphocytic leukemia: final results of a large observational multicenter study in mostly pretreated patients

This retrospective study evaluated the benefit of alemtuzumab monotherapy in unselected patients with advanced B-cell chronic lymphocytic leukemia (CLL) and prolymphocytic leukemia (B-PLL) to definitely describe the impact of this antibody in clinical routine use. Data were collected from 208 consecutive, mainly pretreated, patients with CLL (n?=?202), and B-PLL (n?=?6) who had received alemtuzumab. Response, progression-free survival (PFS), and overall survival (OS) in various settings were assessed, and toxicities were documented. In these routine patients, a comparably low cumulative dose of alemtuzumab (median, 403 mg) was applied. In CLL, overall response rate was 32 %, and various pre-therapeutic parameters were predictive for inferior response, among them, the prior administration of ≥3 therapy lines (P?<?0.001), refractoriness to fludarabine (P?=?0.002), and bulky lymphadenopathy (P?=?0.003). PFS and OS after start of alemtuzumab were 6.2 and 21.0 months, respectively. Bulky lymphadenopathy was the prominent risk factor for both inferior PFS (P?<?0.001) and OS (P?=?0.002). In B-PLL, four patients experienced a fatal outcome, whereas two patients had some benefit with alemtuzumab. The main adverse effects were CMV reactivation (20 %) and a broad spectrum of infections, which together were the main reasons for treatment interruption and/or premature termination. In conclusion, alemtuzumab administered even at low dose levels was effective but overall considerably toxic in routine CLL patients. We emphasize that alemtuzumab remains an important therapeutic option in subsets of CLL patients.     

Staging and therapy of chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease. Some patients require no therapy and have prolonged survival. Others have brief survival despite intensive treatment. Several staging systems have been developed. These are useful in predicting outcome and need of therapy, but controversies exist. Additional prognostic factors have been identified such as cytogenetics, lymphocyte levels or doubling time, bone marrow morphology, and others. Patients with low-stage CLL have not been shown to benefit from treatment. In patients with intermediate disease, combination chemotherapy with cyclophosphamide, vincristine, and prednisone (CVP) has not been shown to be superior to chlorambucil with or without prednisone. The therapy of high stage CLL is controversial; therapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) may be superior to CVP. Future directions of therapeutic research include the treatment of patients with low stage disease, more precise identification of patients requiring therapy, and more precise definition of therapeutic response.