Pentostatin and rituximab therapy for previously untreated patients with B‐cell chronic lymphocytic leukemia

BACKGROUND:

The combination of pentostatin (P), cyclophosphamide (C), and rituximab (R) achieved an overall response (OR) rate >90%, with >40% complete responses (CRs) in patients with untreated chronic lymphocytic leukemia (CLL).

METHODS:

To evaluate whether the tolerability of this regimen could be enhanced without sacrificing efficacy, a phase 2 trial was conducted of P and R without C, using a higher P dose (4 mg/m²). Among the 33 patients enrolled, 82% were male, the median age was 65 years (9 patients were aged ≥70 years), and 64% were classified as having Rai stage III to IV disease.

RESULTS:

The OR rate was 76%, with 9 CRs (27%), 5 nodular partial responses, and 11 partial responses (PRs) reported. At the time of last follow?up, 29 of 33 patients were still alive at a median follow‐up of 14 months (range, 1‐34.8 months). Four (12%) patients experienced grade 3 or higher hematologic toxicity, and 5 (15%) experienced grade 3 or higher nonhematologic toxicity. Comparison of this trial with the previous PCR trial demonstrated that patients treated with PCR had a higher OR rate (91% vs 76%) and CR rate (41% vs 27%) compared with patients treated with PR. The median treatment‐free survival for all accrued patients was notably longer in patients treated with PCR compared with PR (30 months vs 16 months).

CONCLUSIONS:

The findings of the current study suggest that increasing the dose of the purine nucleoside analogue does not eliminate the need for cyclophosphamide in chemoimmunotherapy for the treatment of CLL. Cancer 2010. © 2010 American Cancer Society.     

Combination therapy with fludarabine and rituximab followed by alemtuzumab in the first-line treatment of patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase 2 trial of the Minnie Pearl Cancer Research Network

BACKGROUND: The purpose of the current study was to evaluate the efficacy and toxicity of the combination of fludarabine and rituximab, followed by alemtuzumab, as first-line treatment for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). METHODS: In a nonrandomized phase 2 trial, 41 patients who had previously untreated CLL or SLL and required treatment received 4 cycles of the fludarabine and rituximab combination followed 5 weeks later by 4 weeks (12 doses) of intravenous alemtuzumab therapy. The response to treatment was evaluated after completion of treatment with fludarabine and rituximab, and again after the completion of alemtuzumab consolidation. RESULTS: Initial treatment with the combination of fludarabine and rituximab was well tolerated, and produced a 71% overall response rate (13% complete response). Thirty-four patients began treatment with intravenous alemtuzumab, but this drug was relatively poorly tolerated when given at a short interval after fludarabine and rituximab, and only 20 patients (49% of total) were able to complete the prescribed course. Five patients had an improvement in their response with alemtuzumab; the final complete response rate was 21%. The median progression-free survival for the entire group was 42 months. Toxicity with alemtuzumab included infusion-related toxicity, myelosuppression, and opportunistic infections. CONCLUSIONS: The intravenous schedule of alemtuzumab employed in the trial was relatively poorly tolerated in this community-based trial. The relatively low complete response rates after treatment with the combination of fludarabine and rituximab and after the completion of treatment suggest that these abbreviated courses may compromise efficacy. The generalized use of alemtuzumab as consolidation therapy cannot yet be recommended for community practice. However, optimization of the route of administration, duration of treatment, and interval after completion of induction therapy may improve efficacy, and further investigation is ongoing.     

Treatment of fludarabine‐refractory chronic lymphocytic leukemia

The development of resistance to purine analogs defines a poor‐risk subset of patients with chronic lymphocytic leukemia (CLL). Although in recent years chemoimmunotherapeutic combinations such as fludarabine, cyclophosphamide, and rituximab have induced response rates of 95% in previously untreated patients and increased the rates of failure‐free survival, CLL remains incurable for many patients because of a lack of disease response or the development of refractoriness to fludarabine. Fludarabine‐refractory disease is defined as CLL that does not respond to fludarabine or that recurs within 6 months of treatment with a fludarabine‐containing regimen. The natural course of the disease is associated with poor survival. Salvage therapeutic strategies include alemtuzumab‐containing regimens, targeted agents, and allogeneic stem cell transplantation. Single‐agent alemtuzumab induces response in up to 40% of patients with fludarabine‐refractory CLL, but responses are not durable, and the median survival is approximately 1 to 2 years. Alemtuzumab is also combined with fludarabine, cyclophosphamide, and/or rituximab, and other agents such as lenalidomide and flavopiridol, as well as targeted agents, and used in fludarabine‐refractory CLL. Cumulative evidence suggests that allogeneic stem cell transplantation is an efficacious therapeutic strategy for patients who do not respond to fludarabine or who develop disease recurrence within 12 months after purine analog treatment. In conclusion, chemoimmunotherapy regimens that include alemtuzumab and/or rituximab and allogeneic stem cell transplantation improve the prognosis of this disease, but there is a continued need for novel, more effective therapies. Cancer 2009. © 2009 American Cancer Society.     

Early treatment of high-risk chronic lymphocytic leukemia with alemtuzumab and rituximab

BACKGROUND: Patients with chronic lymphocytic leukemia (CLL) usually are treated only for progressive disease. However, the discovery of biologic predictors of a high risk of disease progression, together with the development of newer, more targeted therapies, could change this paradigm. In this phase 2 study, the authors tested the safety and efficacy of early treatment for patients with high-risk CLL using alemtuzumab and rituximab. METHODS: Patients were eligible for treatment if they were 1) previously untreated, 2) had no National Cancer Institute-Working Group 1996 criteria for treatment, and 3) had at least 1 marker of high-risk disease 17p13-, 11q22-, or a combination of unmutated IgVH and CD38+/ZAP70+). Treatment consisted of subcutaneous alemtuzumab (initial dose escalation followed by 30 mg on Monday, Wednesday, and Friday for 4 weeks) and intravenous rituximab (375 mg/m(2) per week x4 doses). All patients received Pneumocystis pneumonia and herpes virus prophylaxis and were monitored for cytomegalovirus reactivation. RESULTS: Twenty-seven of 30 patients (90%) responded to therapy with 11 (37%) complete responses (CRs). Five patients (17%) patients who had a CR had no detectable minimal residual disease. The median response duration was 14.4 months, and only 9 patients required retreatment for progressive disease at the time of the current report (median follow-up, 17.6 months). Study patients had a significantly longer time from diagnosis to first treatment for CLL according to conventional indications than a comparison cohort with similar biologic risk profiles. CONCLUSIONS: The therapy regimen used was safe and effective for early treatment of patients with high-risk CLL. Further studies will be required to determine whether this early treatment strategy decreases morbidity and mortality for high-risk CLL.     

Update on prophylaxis and therapy of infection in patients with chronic lymphocytic leukemia

Infections remain a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia. These patients are predisposed to infection due to the immune compromise inherent to the primary disease and to therapy-related immunosuppression. The introduction of purine analogs and agents such as Campath-1H into the therapeutic armamentarium for chronic lymphocytic leukemia has altered the spectrum of infections. Although bacterial infections are most common, opportunistic infections, such as those caused by Candida, Pneumocystis and herpesviruses, may occur, related to T-cell immunosuppression induced by these agents. We will review the pathogenesis of infection, spectrum of infections, risk factors for infection and approaches for infection prophylaxis and therapy.     

Monoclonal antibodies in chronic lymphocytic leukemia

Multiple options are now available for the treatment of chronic lymphocytic leukemia. Over the last 10 years, monoclonal antibodies have become an integral part of the management of this disease. Alemtuzumab has received approval for use in patients with fludarabine-refractory chronic lymphocytic leukemia. Rituximab has been investigated extensively in chronic lymphocytic leukemia both as a single agent and in combination with chemotherapy and other monoclonal antibodies. Epratuzumab and lumiliximab are newer monoclonal antibodies in the early phase of clinical development. This article will review the monoclonal antibodies more commonly used to treat chronic lymphocytic leukemia, the results obtained with monoclonal antibodies as single agents and in combination with chemotherapy, and other biological agents and newer compounds undergoing clinical trials.     

Monoclonal antibodies in the treatment of chronic lymphocytic leukemia

Traditional therapy for chronic lymphocytic leukemia (CLL) has consisted of alkylating agents, purine analogs, or a combination of these drugs. These agents are effective at producing remissions but are not curative. Thus, new drugs are still needed to improve the outcome of patients with CLL. The introduction of monoclonal antibodies, such as rituximab and alemtuzumab, provides a novel therapeutic modality. Rituximab is an active agent in CLL. Standard doses of rituximab result in higher response rates in previously untreated than in relapsed patients but low complete response (CR) rates. Rituximab is most effective in combination with chemotherapy, especially fludarabine-based regimens in the first-line and salvage setting. Rituximab is also useful in the treatment of complications of CLL, such as pure red cell aplasia, autoimmune thrombocytopenia, and autoimmune hemolytic anemia. Alemtuzumab has impressive activity in patients with refractory CLL and may play an important role in the consolidation treatment of CLL. Alemtuzumab is most efficacious at clearing disease in the peripheral blood and bone marrow. Bulky lymphadenopathy is less sensitive to therapy. Because of the significant lymphopenia associated with alemtuzumab, antibacterial and antiviral prophylaxis should always be used.     

Chronic lymphocytic leukemia

Patients with purine analogue–refractory chronic lymphocytic leukemia (CLL) have short survival and limited treatment options. Defining the best salvage strategies for this population is challenging, because limited data are available from clinical trials, and because studies have enrolled mixed populations (patients with recurrent and refractory disease or patients with refractory disease and Richter transformation). Moreover, patients with refractory CLL have a high incidence of unfavorable molecular and clinical features, such as high‐risk genomic profiles, unmutated immunoglobulin heavy‐chain genes, expression of zeta‐chain–associated protein kinase 70, and bulky lymphadenopathies. These patients are also severely immunosuppressed because of the underlying disease and the treatments received, and experience a high rate of infectious complications that pose an additional difficulty in selecting treatment. Despite these challenges, in parallel with better characterizations of the biologic features of refractory CLL, the number of available treatment modalities for this population has increased. Several chemoimmunotherapy combinations have been developed, and novel agents with a different mechanism of action are being investigated in clinical trials. Furthermore, allogeneic stem cell transplantation with nonmyeloablative conditioning regimens is a therapeutic strategy that is increasingly offered to patients with refractory CLL. Cancer 2009. © 2009 American Cancer Society.     

Progress in the treatment of chronic lymphocytic leukemia: results of the German CLL8 trial

Until now, no approach that is able to improve overall survival of chronic lymphocytic leukemia (CLL) patients has been available. In the German CLL Study Group (GCLLSG) CLL8 trial, treatment-naive, physically fit patients (aged 30–81 years) with CD20⁺ CLL were randomly assigned in a one-to-one ratio to receive six courses of intravenous fludarabine (25 mg/m² per day) and cyclophosphamide (250 mg/m² per day) for the first 3 days of each 28-day treatment course with or without rituximab (375 mg/m² on day 0 of first course and 500 mg/m² on day 1 of second to sixth courses). The two groups were well balanced with respect to baseline characteristics. The study was stopped at the preplanned interim analysis owing to an advantage in the median progression-free survival in the chemoimmunotherapy arm (51.8 vs 32.8 months; hazard ratio: 0.56; 95% CI: 0.46–0.69; p < 0.0001). Furthermore, at 3 years after randomization, 87% of patients in the chemoimmunotherapy group were alive compared with 83% in the chemotherapy group (hazard ratio: 0.67; 95% CI: 0.48–0.92; p = 0.01). In terms of toxicity, chemoimmunotherapy was more frequently associated with grade 3 and 4 neutropenia (p < 0.0001). There were eight (2%) treatment related-deaths in the chemoimmunotherapy arm compared with ten (3%) in the chemotherapy arm. The CLL8 trial has demonstrated that an association of rituximab, fludarabine and cyclophosphamide is effective in prolonging progression-free survival and overall survival of patients with symptomatic CLL, therefore establishing the new standard of treatment for physically fit patients.     

Selective BTK inhibition improves bendamustine therapy response and normalizes immune effector functions in chronic lymphocytic leukemia

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been shown to be highly effective in patients with chronic lymphocytic leukemia (CLL) and is approved for CLL treatment. Unfortunately, resistance and intolerance to ibrutinib has been observed in several studies, opening the door for more specific BTK inhibitors. CC-292 (spebrutinib) is a BTK inhibitor with increased specificity for BTK and less inhibition of other kinases. Our in vitro studies showed that CC-292 potently inhibited B-cell receptor signaling, activation, proliferation and chemotaxis of CLL cells. In in vivo studies using the adoptive transfer TCL1 mouse model of CLL, CC-292 reduced tumor load and normalized tumor-associated expansion of T cells and monocytes, while not affecting T cell function. Importantly, the combination of CC-292 and bendamustine impaired CLL cell proliferation in vivo and enhanced the control of CLL progression. Our results demonstrate that CC-292 is a specific BTK inhibitor with promising performance in combination with bendamustine in CLL. Further clinical trials are warranted to investigate the therapeutic efficacy of this combination regimen.     

The role of chemotherapy in managing chronic lymphocytic leukemia: optimizing combinations with targeted therapy

For many years, alkylating agents were the standard treatment for chronic lymphocytic leukemia (CLL). The advent of purine analogs improved response rates, but not overall survival, and although the monoclonal antibody rituximab is generally active against B-cell malignancies, it has demonstrated limited benefits as monotherapy for the treatment of CLL. However, specific combinations of chemotherapy, antibodies and targeted therapies have demonstrated additive or synergistic activity in CLL cells and deliver substantial clinical benefits. A greater understanding of the actions of chemotherapies and targeted agents on cellular pathways will advance the development of rationally designed combinations corresponding to individual patients’ disease profiles.     

Idiopathic thrombocytopenic purpura and myasthenia gravis after fludarabine treatment for chronic lymphocytic leukemia

We report a patient with chronic lymphocytic leukemia (CLL) who developed idiopathic thrombocytopenic purpura (ITP) and myasthenia gravis (MG) after fludarabine therapy. ITP developed after 6 cycles of fludarabine treatment, and MG occurred 2 months after the onset of ITP. MG was successfully treated with immunosuppressive therapy and plasma exchange, while rituximab was effective for CLL and ITP. Fludarabine seemed to have an important role in the onset of ITP and MG in this case.     

Accelerated growth of skin carcinoma following fludarabine therapy for chronic lymphocytic leukemia

We present four patients with chronic lymphocytic leukemia treated with fludarabine, who developed aggressive skin cancer after years of quiescence, a short time after institution of treatment. Their leukemias responded well to therapy with fludarabine with initial treatment as well as relapse. Three patients had recurrence with basal cell carcinomas with multiple, rapidly growing tumors and one had recurrence of both basal and squamous cancers and eventually died of metastatic squamous cell carcinoma. Fludarabine induces prolonged period of lymphopenia, affecting especially the T cell population, which is crucial in the defense against skin cancers. There appears to be a direct association between fludarabine and the flare up of skin cancers in these patients, possibly analogous to the increased incidence of these malignancies in patients on chronic cyclosporine immunosuppression.     

Choosing first-line therapy for chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) exhibits a highly variable natural history, but the addition of genomic risk stratification to traditional clinical staging systems has begun to explain the heterogeneous clinical course. Overall response to treatment has significantly improved over the past three decades and for the first time, a survival benefit has been demonstrated with the use of monoclonal antibodies in combination with cytotoxic chemotherapy. Newer therapeutic strategies have abrogated the adverse prognosis associated with some higher risk features, but other genetic subgroups remain at high risk for rapid disease progression and early mortality. Patients at advanced age or with significant comorbidity constitute a large proportion of the CLL population and present unique clinical challenges. This article will discuss the evolution of contemporary therapeutic approaches to the initial treatment of CLL, and highlight the ways in which risk-adapted therapeutic strategies are improving clinical outcomes.     

Self‐administered,subcutaneous alemtuzumab to treat residual disease in patients with chronic lymphocytic leukemia

BACKGROUND:

Alemtuzumab is highly effective at treating chronic lymphocytic leukemia (CLL) in bone marrow, which is the usual site of residual disease after fludarabine‐based treatment. Eliminating residual disease potentially is associated with longer remission and overall survival. The authors of this report evaluated the ability of subcutaneous alemtuzumab to treat residual disease.

METHODS:

Patients in partial remission (PR), nodular PR (nPR), or complete remission (CR) who had disease in bone marrow established by 2‐color flow cytometry analysis were enrolled and received alemtuzumab 30 mg subcutaneously 3 times weekly for 4 weeks, and patients had the option to self‐administer alemtuzumab. Responders were patients in PR who converted to an nPR or a CR, patients in nPR who converted to a CR, and patients in CR who had no evidence of disease on 2‐color flow cytometry analysis after treatment.

RESULTS:

There were 31 patients enrolled, of whom 29 were evaluable, and there were 23 responders (4 of 4 patients who achieved a CR, 8 of 9 patients who achieved an nPR, and 11 of 16 patients who achieved a PR. Nonresponders had significantly lower plasma alemtuzumab levels at the end of treatment. Furthermore, higher plasma alemtuzumab levels at the end of treatment were correlated with a longer response duration. Compared with the results from an historic group that received intravenous alemtuzumab for residual disease, there was a trend toward a higher response rate but a shorter response duration with subcutaneous alemtuzumab.

CONCLUSIONS:

The current results demonstrated that self‐administered, subcutaneous alemtuzumab was safe and active for residual disease and that plasma alemtuzumab levels and real‐time minimal residual disease evaluation are important endpoints to monitor in future alemtuzumab consolidation trials. Cancer 2011. © 2010 American Cancer Society.