Alemtuzumab in the up-front setting

Alemtuzumab in the up-front setting

The management of chronic lymphocytic leukemia (CLL) has evolved dramatically in the last decade. In this setting, toxoplasmosis typically manifests as multiple abscesses readily seen on routine neuroimaging studies. We undertook this study to assess whether a diagnosis of herpes zoster is a risk factor for subsequent malignancy. Unfortunately, there are hardly any data on the use of prophylactic antibiotics for patients with chronic lymphoid malignancy (CLL). Pentostatin was evaluated in combination with orally administered chlorambucil 30 mg/m2 and prednisone 80 mg/day, 1-5 of each 14-day cycle. His only medications were omeprazole and acetaminophen of which he had been taking 500 mg every 4 to 6 hours for about 2 months for what was believed to be postherpetic neuralgia. Six patients with B-CLL (M : F = 4 : 2; mean age: 67.8) presented with specific skin lesions located on the nipple (four cases) and scrotum (two cases).

Alemtuzumab is a humanized chimeric monoclonal antibody targeting CD52. The cutaneous infiltrate of neoplastic cells seemed to be part of a physiologic response to the antigenic stimulus, rather than indicating an exacerbation of leukemia. Most experience using alemtuzumab has been in the relapsed and refractory setting. One patient who was in partial response status progressed 5 months after transplantation, and the other 3 patients remained in durable remission after allo-HSCT. Alemtuzumab’s particularly good activity in high risk patients at clearing peripheral blood, bone marrow and spleen of CLL cells have led to its consideration in the first-line setting. Four patients showed grade 2 skin reaction at the site of the subcutaneous injection and grade 1 or 2 fever. Despite its approval in both upfront and relapsed settings, alemtuzumab’s role in CLL treatment continues to evolve.

Ample evidence of alemtuzumab’s efficacy in difficult patient populations and in specific disease scenarios have ultimately led to its examination in the front-line setting. In 1997, Osterborg et al (1997) published the results of a European, multi-center trial in 1997 using single-agent alemtuzumab in 29 CLL patients who had relapsed after first-line treatment or who had refractory disease. The overall response rate was 41% and complete response was 4%. Its efficacy at clearing CLL cells from the peripheral blood (97% of patients) and from the bone marrow (36% of patients) was particularly notable. The 5-year survival of patients with small-cell cutaneous B-CLL was 66.6%. On the other hand, lymph nodes were reduced to normal in only 2%. Rai et al (2002a) published a study in which 24 fludarabine-refractory patients received single-agent alemtuzumab and obtained a response-rate of 33% (there were no complete responses).

Also in 2002, Keating et al (2002) published data from the CAM211 trial in which 93 fludarabine-refractory patients received alemtuzumab and achieved a 33% overall response rate. Initial therapy with a monoclonal antibody, such as rituximab (in high doses or more frequent scheduling) with or without maintenance rituximab, is consistent with this strategy. A response rate of 54% was achieved in fludarabine-refractory patients with the unfavorable mutation 17p deletions or p53 abnormalities. A subsequent trial performed by Lozanski et al (2004) found a 31% response in patients with this high-risk profile. Alemtuzumab’s use in combination with other agents also showed impressive results in refractory disease. The combination of alemtuzumab and fludarabine was examined in trials published by Kennedy et al (2002) (n = 6) and Elter et al 2005) (n = 36). The association with TREANDA therapy has not been determined.

Faderl et al (2003) used alemtuzumab in combination with rituximab in this population and achieved a response rate of 63%. CD38 signals start upon interaction with the CD31 ligand expressed by stromal and nurse-like cells. At the time of diagnosis made in this case report, extensive extracutaneous involvement was present. Chemotherapy targets growing cells, interfering with their ability to divide or multiply. In 1967, Dameshek hypothesized that CLL was an accumulative disease of immunologically incompetent lymphocytes.15 In the early 1970s, the leukemic cells from most cases of CLL were found to express surface immunoglobulin, indicating that the neoplastic cells were of B-cell origin.16 Subsequent studies demonstrated that the CLL cells of female patients who were heterozygous for glucose-6-phosphate dehydrogenase (G6PD) expressed only one G6PD allele,17 indicating that the leukemia cells arose from a single B-cell clone. Duration of response ranged from 8 to 24 months. burgdorferi DNA using the polymerase chain reaction (PCR) technique.

Single-agent alemtuzumab was administered subcutaneously thrice weekly for 18 weeks to 41 patients as first-line treatment. Thirty-eight patients responded to therapy, for an overall response rate of 87 % ( 95% CI, 76%–98%) – 19% achieved a complete remission and 68% achieved a partial remission. 95% of patients cleared CLL cells in their peripheral blood at a median of 21 days of treatment, and 66% achieved CR or nodular PR in the bone marrow after the full course of 18 weeks of treatment. 2006. There were transient injection-site skin reactions in 90% of patients. Results of an international prospective, randomized, controlled trial comparing alemtuzumab to chlorambucil as front-line therapy was reported at the American Society of Hematology annual meeting in 2006 (Hillmen et al 2006) and published in December 2007 (Hillmen et al 2007). Treating the underlying malignancy with chemotherapy may help to control autoantibody production.

We need organized and functional T cells, something we are often sorely missing. The alemtuzumab arm showed an overall response rate of 83% compared to a 55% response rate in the chlorambucil arm. Complete responses were seen in 24% and of the alemtuzumab arm and 2% of the chlorambucil arm. MRD negativity was achieved in 11 of 36 complete responders in the alemtuzumab arm vs none in the chlorambucil arm. Time to alternative treatment was 23.3 months for the alemtuzumab arm vs 14.7 months for the chlorambucil arm (p = 0.0001). The probability of a patient responding was associated with their degree of lymphadenopathy. Of the 282 patients who had cytogenetic analysis, 231 patients (82%) revealed abnormalities, including 19% with 11q deletions, 7% with 17p deletions and 14% with trisomy 12 (Robak et al 2006).

Patients receiving one or more cycles of therapy were assessable for toxicity. Overall response rates for these two groups were 64% and 20%, respectively. Notably, none of these patients had active GVHD and none were receiving immunosuppressive therapy with the exception of two patients who received dexamethasone along with maintenance lenalidomide. PFS was 8.5 months in both arms. Clin Lab Haematol 1995; 17:75-80. These two groups had similar response rates of 83% in the alemtuzumab arm and 80% in the chlorambucil arm. Of particular note, however, is that although these benefits for patients with high risk cytogenetics were statistically significant in terms of response, this did not extend to PFS.

Viral infections (11 out of 88 infections; 12.5%) developed in 8 patients. There is a special name for it, post-herpatic neuralgia. If it is not contra-indicated in your case, that is. CMV viremia occurred in 52% of patients on the alemtuzumab arm and 16% had symptomatic CMV infections. Only 7.5% of patients on the chlorambucil had evidence of CMV viremia by PCR, none of whom were symptomatic. Although this trial adds important data in terms of the use and activity of alemtuzumab as single-agent in the front line, the results must be cautiously interpreted due to its relatively short median follow-up of only 24.6 months, and the fact that 84% of patients in each arm remain alive. Notably, patients who had ZAP70 expression by IHC had a lower CR rate compared with those who did not (57% vs 94%).
Alemtuzumab in the up-front setting

Eight patients experienced 12 events of grade 3 diarrhea, with 3 patients having ≥1 occurrence. The primary analysis was based on the number of complete and partial response rates and their 95% exact binomial confidence intervals. In 1997 Dyer et al (1997) published a small study of 6 CLL patients who were treated with fludarabine, had persistent disease in the bone marrow, and then were treated with alemtuzumab. Five of the 6 patients achieved a hematologic and histological complete remission following alemtuzumab. As mentioned above, rituximab is currently being used in combination with chemotherapy. Lenalidomide is an oral immunomodulatory agent with response rates over 50%, with or without rituximab, for patients with previously treated and untreated disease.[Level of evidence: 3iiiDiv] Prolonged, lower-dose approaches and attention to prevention of tumor lysis syndrome are suggested with this agent. 1991;4(8):770-776.

Whether the CLL has recurred (come back). Fifteen patients (37%) were reported to have infectious complications, 9 of which were CMV reactivations. At the annual meeting of the American Society of Clinical Oncology in 2005, Wendtner et al (2004) and the German CLL Study Group presented the results of a trial that randomized patients who responded to fludarabine/cyclophosphamide or fludarabine alone to either alemtuzumab 30 mg subcutaneous 3 times per week for 12 weeks or observation. The trial was ultimately stopped early due to severe infectious toxicities. Of the 21 evaluable patients, 11 were randomized to receive alemtuzumab. Patients in the alemtuzumab arm showed a significantly longer PFS compared to those in the observation arm (no progression at a median of 21.4 months follow up vs 24.7 months). Seven of the 11 patients on the alemtuzumab arm had infectious complications including one life-threatening case of pulmonary aspergillosis, 4 patients with CMV reactivation (2 with clinically evident CMV pneumonia), 1 tuberculosis and 1 herpes zoster infection.

A recent German CLL Study Group study (Stilgenbauer and Dohner, 2002) demonstrated similar efficacy of alemtuzumab (30 mg SQ) three times weekly for 12 weeks when compared to historical data where the same total dose of alemtuzumab was administered i.v. Although these patients were previously treated, consolidation proved to be an attractive concept in the front-line setting as well. The practice guideline that specifically addressed alemtuzumab use indicated that it was developed out of an expert-opinion roundtable on the topic held August 8–9, 2004). Thirty-six per cent obtained a complete remission, including 20 % (n = 18) who had obtained MRD negativity by flow cytometry. The Spanish CLL Study Group recently presented the final results of a Phase 2 clinical trial evaluating rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) followed by rituximab maintenance for front-line treatment of CLL.61 Patients achieving a CR or PR after 6 cycles of R-FCM received rituximab maintenance every 3 months (375 mg/m2) for 2 years. MRD negative patients had not reached median overall survival vs median overall survival of 60 months for those patients that obtained CR but not MRD negativity. However, the Ontario Cancer Registry has undergone extensive validation.27 The large number of exposed cases and unexposed controls means that statistical significance may have been found even for small absolute differences.

It remains unclear as to whether achievement of MRD-negativity itself results in a better outcome, or if the ability to clear the bone marrow simply represents a group of patients with more sensitive disease. The issue is still being debated. The Cancer and Leukemia Group B (CALGB) conducted a study using alemtuzumab following fludarabine in the first-line (Rai et al 2002b, 2003). Fifty-six patients were enrolled and received 4 monthly cycles of single-agent fludarabine. Patients that achieved stable disease or better after 2 months of observation following fludarabine received alemtuzumab 30 mg intravenously TIW for 6 weeks, intravenously. Another 24 patients underwent the same fludarabine regimen, but received alemtuzumab subcutaneously if a response was achieved. In the first group (designated to receive intravenous alemtuzumab), 36 of the 56 patients ultimately received alemtuzumab IV.

Fifteen of those 36 improved to CRs (42%) and 18 had PRs (50%) for an overall improvement of response rate to 92%. Of the 24 patients in the second (subcutaneous alemtuzumab) group, 18 patients qualified to get subcutaneous alemtuzumab. Of those 18 patients, 12 (66%) improved their response, including 22% who achieved CRs and 44% who achieved PRs. Mantillo et al also examined the achievement of MRD negativity following alemtuzumab consolidation in a phase II study of 34 patients (Montillo et al 2006). Patients who had a clinical response to fludarabine-based therapy in the front-line received alemtuzumab 10 mg subcutaneously TIW for 6 weeks. Patients went on to have stem cell mobilization for transplant. Following treatment with the alemtuzumab, the CR rate improved from 35% after the fludarabine treatment to 79%.

Nineteen patients (56%) achieved MRD negativity. There was CMV reactivation in 18 patients, all of whom were successfully treated with antiviral therapy. Twenty-four of these patients underwent successful stem cell collection and 18 underwent autologous bone marrow transplant. Alemtuzumab has well-known infectious complications. As described in the pivotal trials above, major infectious complications were observed in approximately half of the patients (Keating et al 2002; Rai et al 2002a). These infections included septicemia, opportunistic infections such as aspergillosis, Pneumocystis carinii, herpes simplex (re)activations, and cytomegalovirus. Generally, these infectious complications have been found to be more common in patients who are not responding to alemtuzumab thereapy (Rai et al 2002a; Montillo et al 2006).

In one study, Rai et al found major infections in only 2 of 8 responders, compared with 8 of 16 nonresponders. A retrospective evaluation of 27 patients treated for lymphoid malignancies at Dana Farber/Brigham and Women’s Hospital found that 56% (15 of 27) experienced opportunistic infections (including CMV(44%), progressive multifocal leukoencephalopathy, adenovirus, toxoplasmosis, and acanthamaebiasis). In addition, 30% nonopportunistic infections were found in 22 patients (Martin et al 2006). These complications are particularly common when alemtuzumab is combined with purine analogs (Keating et al 2002). Cytomegalovirus (CMV) infection is the most common complication. The ability to signal via surface IgM (sIgM) varies between the main subsets of CLL and is associated with expression of ZAP-70. In a search of the recent scientific literature, a few cases of various lymphomas arising in herpes zoster scars have been reported.

For this reason, people who have repeated infections may be treated with intravenous immune globulin (also called IVIG or IGIV) to increase their immunoglobulin levels and decrease the chance of infection. 84). Typically, if CMV is detected, or if there is a high suspicion on infection, alemtuzumab is temporarily held and antiviral therapy is initiated. Some debate does exist as to what point alemtuzumab should be held and restarted. Published guidelines by O’Brien et al (2006) suggest that alemtuzumab be held only in the setting of severe infection or persistent symptoms. Once signs and symptoms of infection have resolved, the therapy should be restarted. Both symptomatic and asymptomatic CMV in these patients usually responds to gancyclovir.

Prophylaxis for prevention of varicella zoster and herpes simplex reactivation, as well as for pneumocystis carinii pneumonia, should also be given throughout treatment. These prophylactic antibiotics and CMV monitoring should be continued following alemtuzumab for approximately 6–8 months, and at least until recovery of CD4+ T-cells. Alemtuzumab’s role continues to expand. Early trials showed alemtuzumab’s value in refractory disease and helped to define its excellent activity in the bone marrow, spleen and 17p deleted patients. With this data, additional trials were developed in an attempt to further expand its role. The CAM307 trial has demonstrated alemtuzumab’s efficacy as monotherapy in the front-line setting. Especially promising is the trend toward improved response in patients with high risk cytogenic abnormalities (particularly 17p del).

This trend requires further investigation but notwithstanding, alemtuzumab is a reasonable first-line choice for this population. The various consolidation trials have also provided promising results of achieving eradication of minimal residual disease (MRD). Infections after the cessation of alemtuzumab in non-MRD-negative CR patients occurred after a median of 9 months (range, 1 to 41 months) and in the MRD-negative patients after a median of 3 months (range, 1 to 12 months).

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