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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Royal Marsden NHS Trust, London, United
Kingdom; Hopital C. Huriez, Lille, France; National Hospital, Oslo,
Norway; Institute of Oncology, Lisbon, Portugal; Hospital Clinic,
Barcelona, Spain; University of Ancona, Italy; Southampton University
Hospital, Southampton, United Kingdom; Greenwich Hospital, London,
United Kingdom; Queen Mary's Hospital, Sidcup, Kent, United Kingdom;
Worthing Hospital, Sussex, United Kingdom; and Centre of Oncology,
Lausanne, Switzerland.
T-cell prolymphocytic leukemia (T-PLL) is a chemotherapy-resistant
malignancy with a median survival of 7.5 months. Preliminary results
indicated a high remission induction rate with the human CD52 antibody,
CAMPATH-1H. This study reports results in 39 patients with T-PLL
treated with CAMPATH-1H between March 1993 and May 2000. All but 2 patients had received prior therapy with a variety of agents, including
30 with pentostatin; none achieved complete remission (CR). CAMPATH-1H
(30 mg) was administered intravenously 3 times weekly until maximal
response. The overall response rate was 76% with 60% CR and 16%
partial remission (PR). These responses were durable with a median
disease-free interval of 7 months (range, 4-45 months). Survival was
significantly prolonged in patients achieving CR compared to PR or no
response (NR), including one patient who survived 54 months. Nine
patients remain alive up to 29 months after completing therapy. Seven
patients received high-dose therapy with autologous stem cell support,
3 of whom remain alive in CR 5, 7, and 15 months after autograft. Stem
cell harvests in these patients were uncontaminated with T-PLL cells as
demonstrated by dual-color flow cytometry and polymerase chain reaction. Four patients had allogeneic stem cell transplants, 3 from
siblings and 1 from a matched unrelated donor. Two had nonmyeloablative
conditioning. Three are alive in CR up to 24 months after allograft.
The conclusion is that CAMPATH-1H is an effective therapy in T-PLL,
producing remissions in more than two thirds of patients. The use of
stem cell transplantation to consolidate responses merits further study.
(Blood. 2001;98:1721-1726) T-cell prolymphocytic leukemia (T-PLL) is a rare
aggressive postthymic malignancy with distinctive clinical,
morphologic, and cytogenetic features.1 T-PLL is often
resistant to conventional chemotherapy and has a poor median survival
(7.5 months).1 Although some patients may initially
present with indolent disease, they eventually progress and the outcome
is then similar.2 New therapeutic approaches are badly
needed to improve outcome in this fatal disease.
CAMPATH-1H is a genetically reshaped human IgG1 anti-CD52 monoclonal
antibody, consisting of the hypervariable regions of the parental rat
antibody inserted into the framework regions of normal human
immunoglobulin (IgG1) genes.3 The CD52 antigen is a nonmodulating glycosylphosphatidylinositol (GPI)-linked protein of
unknown function abundantly expressed on normal and malignant lymphocytes, monocytes, macrophages, and eosinophils, but not on
hemopoietic progenitor cells.4 In vitro, CAMPATH-1H is
active in complement-mediated lysis and antibody-dependent cellular
cytotoxicity (ADCC). Both these mechanisms may contribute to the
therapeutic activity of this antibody in vivo. CD52+ cells
vary in their sensitivity to lysis induced by CAMPATH-1H and this may
be related to the antigen site density on different cell
types.5
Promising results have been obtained using CAMPATH-1H antibodies in
patients with a variety of lymphoproliferative
disorders.6,7 These early studies included a patient with
T-PLL who went into complete remission (CR) with the rat IgG2b antibody
CAMPATH-1G.6 This prompted a larger phase 2 study to
examine the role of CAMPATH-1H in this disease.8 We have
now extended this study to include 39 patients and have also examined
the use of high-dose treatment with autologous or allogeneic stem cell
transplantation (SCT) in 11 patients.
Patients
Diagnosis was confirmed by morphology of peripheral blood and bone
marrow (BM) smears, immunologic markers, and histology (BM and spleen).
Treatment
Response evaluation A CR was defined as the absence of disease detectable by morphology of blood and BM (including trephine biopsy) and computed tomography (CT) scanning. PR was defined as 50% or more reduction in detectable disease, but short of a CR, maintained for 2 months or more. Detection of minimal residual disease by flow cytometry and polymerase chain reaction (PCR) was not included in the response criteria.Disease-free interval (DFI) was measured from the end of CAMPATH-1H therapy to the time of relapse. Event-free survival (EFS) was measured from start of treatment to any event. Overall survival was determined from start of treatment to last follow-up or day of death. The analysis was conducted using the method of Kaplan and Meier.
Responses Thirty-eight patients were evaluable for response (Table 1). Patient 39 died suddenly, probably from intracranial hemorrhage, 2 weeks after commencing treatment. The overall response rate was 76%, with 60% CR and 16% PR (Table 2). These responses were durable, with a median DFI of 7 months (range, 4-45 months). Thirteen (34%) patients who had previously been resistant to chemotherapy, including 9 who had NR to pentostatin, achieved a CR following CAMPATH-1H. Figure 1 shows the responses according to site. Clearance of malignant cells from blood and BM was generally rapid although tumor lysis syndrome was not observed in any patient. Resolution of splenomegaly and skin infiltration occurred in half the affected patients and lymphadenopathy in 43%. However, patients with serous effusions and hepatic or central nervous system (CNS) involvement had a poor response to therapy. Patients with very bulky lymph node masses were also more resistant to treatment. In patient 19, CNS disease was effectively cleared by use of intrathecal triple therapy (methotrexate, cytosine arabinoside, and hydrocortisone) prior to commencing CAMPATH-1H treatment. There was no statistical difference in response according to patient age, sex, or presenting white blood cell count (WCC). Patients 5 and 17 received CAMPATH-1H after achieving a PR with prior therapy (pentostatin) and obtained a molecular remission followed by SCT (autograft, patient 5; allograft, patient 17).
Of 12 patients who were retreated with CAMPATH-1H following relapse, 5 (42%) achieved a second CR, and one a PR, with responses lasting 5 to 6 months. One of these patients (no. 5) had been treated for a molecular relapse, without any other evidence of disease. There was no statistical difference in the length of first CR or other disease characteristics, comparing the patients who did or did not have a second response. Nine (23%) of the 39 patients entered into the study remain alive. Of
the patients who died, 4 died while still in CR, 1 from carcinoma of
the stomach (patient 23), 1 from multiple arterial thromboses (patient
13), 1 from infection (patient 4), and 1 from treatment-related
toxicity (allogeneic bone marrow transplant, patient 17); 1 died from
amyotrophic lateral sclerosis but had also relapsed (patient 14); the
remainder died from progressive disease. The median overall survival
for the whole group was 10 months (Figure
2). Survival was significantly prolonged
in those patients achieving CR (median, 16 months) compared to partial (median, 9 months) and nonresponders (median, 4 months)
(P = .00066; Figure 3). This
observation holds true when the analysis is performed on
patients surviving at least 3 months (P = .01380)
adjusting for the confounding effect of early deaths (Figure
4). Patients 1 and 2 survived for more than 4 years following treatment.
Immunology and cytogenetics The malignant T cells from 13 patients (33%) were CD4+/CD8 , CD4+/CD8+
in 16 (41%), and CD4/CD8+ in 9 (23%). All
cases tested were CD52+ at diagnosis, although cells from
patients 10 and 11 were found to have lost CD52 expression at relapse
and became resistant to further CAMPATH-1H therapy.
Twenty-eight patients (72%) had successful cytogenetic analysis; 2 had a normal karyotype, and the remainder had complex abnormalities. The most consistent abnormalities involved chromosome 14 including 15 patients with inv(14)(q11q32), 3 with t(14;14)(q11;q32), 2 with del(14)(q12) and 1 t(11;14)(q23;q11). Eleven patients had idic(8)(p11); in 8 patients this was found in association with inv(14)(q11q32), in 2 with t(14;14)(q11;q32) and in 1 with del(14)(q12). There was no correlation between overall or complete responses to CAMPATH-1H and immunophenotype or karyotype. Autograft and allograft Seven patients (18%) have proceeded to high-dose therapy (melphalan or cyclophosphamide and total body irradiation [TBI] or BCNU, etoposide, cytarabine, melphalan [BEAM]) with autologous SCT. Stem cell harvests (in 6 of 7 tested) were uncontaminated with T-PLL cells as demonstrated by dual-color flow cytometry and PCR for T-cell receptor (TCR) gene rearrangements. Patients 1 and 2 were autografted in their second remission. Patients 1, 2, 6, and 11 have subsequently relapsed after 5 to 14 months and died from progressive disease. Patients 5, 16, and 19 remain alive 5+, 7+, and 15+ months after autograft.Four patients (10%) have had an allogeneic SCT (3 sibling [patients
17, 21, and 37], 1 matched unrelated donor [MUD; patient 28]). Two
of the allografts (patients 28 and 37), including the MUD transplant,
were performed using a nonmyeloablative conditioning regimen.9 Three patients are alive in CR, one of whom
remains in molecular remission 2 years after transplant (patient 21). One died (patient 17), while still in remission, from treatment-related toxicity. Patient 37 had been resistant to initial induction therapy including CAMPATH-1H but achieved a good PR following BEAM chemotherapy and went on to receive a sibling allograft using a nonmyeloablative conditioning regimen. He remains well 11 months after
transplant having received one donor lymphocyte infusion to maintain
full donor chimerism. The mini-MUD transplant was performed on patient 28, who had only achieved PR to CAMPATH-1H and was showing signs of
disease progression. These 2 cases illustrate the potential for
allografting as salvage therapy in patients with refractory disease.
Results are shown in Table 3.
Toxicity First-dose reactions characterized by fever, rigors, and nausea (grade 1/2) occurred in all patients, but no serious allergic reactions were observed. Rigors responded to treatment with Demerol. Urticaria was seen in 9 patients (23%) but was usually mild and transient. No patient experienced significant fluid retention. The major side effect of CAMPATH-1H therapy was prolonged lymphopenia (grade 4) lasting for up to 320 days after completion of CAMPATH-1H. Opportunistic infections included 1 case of cryptococcal meningitis, 1 cytomegalovirus (CMV) reactivation, 2 herpes zoster (1 case complicated by myelitis and retinitis), 2 Pneumocystis pneumonia (1 unconfirmed), and 1 Legionella pneumonia. These patients all recovered following appropriate therapy. One patient died from an unidentified pulmonary infection during a second course of CAMPATH-1H given to treat disease relapse.Transient hematologic toxicity (grades 3 and 4) was documented in 5 patients (13%). Four of these patients had an isolated thrombocytopenia and in one case there was a concomitant fall in hemoglobin and neutrophil count. The blood count recovered to normal within 14 days in all 5 patients. Prolonged pancytopenia with severe BM aplasia was seen in a further 2 patients, one of whom died from a fungal pneumonia.
Our results confirm earlier observations that T-PLL is particularly responsive to treatment with the monoclonal antibody CAMPATH-1H.8 Overall (76%) and complete (60%) response rates are significantly higher than those reported previously for conventional therapies such as CHOP, with which a third of patients achieve short-lived responses (3 months) or pentostatin with a 40% overall response (12% CR).10 In those patients responding to CAMPATH-1H clearance of cells from the peripheral blood was rapid. However, in no case was this complicated by tumor lysis syndrome. Although many of the CRs were durable (up to 45 months) and survival was prolonged, there is no evidence that CAMPATH-1H therapy alone alters the ultimate fatal outcome for patients with this aggressive malignancy. All but 2 patients followed up for more than a year have relapsed, including all but one of those who have received autografts with ostensibly uncontaminated stem cells. CAMPATH-1H is not therefore curative despite second responses. Consolidation therapy in first remission with autologous or allogeneic transplantation appears to prolong the DFI and improve survival. However, relapse after autograft seems to be inevitable. Because some stem cell harvests have been shown to be negative for T-PLL by PCR, these relapses may arise from other "sanctuary" sites where CAMPATH-1H is ineffective at clearing disease. The graft-versus-leukemia (GVL) effect seen in allogeneic SCT is likely to be important and patients who are eligible for this treatment may be potentially curable.11 Because T-PLL patients are often over the age of 55 years the use of a nonmyeloablative conditioning may make allogeneic transplantation a possibility for a larger proportion of patients. This strategy may also be able to salvage patients who are resistant to first-line therapy. Experience using CAMPATH-1H in the treatment of non-Hodgkin lymphoma and chronic lymphocytic leukemia (CLL) has shown that, although clearance of disease from blood and BM may be complete, bulky disease at other sites (lymph nodes, liver, CNS) may be resistant.12-16 This differential pattern of response may reflect poor accessibility of the antibody to tumor cells in different sites or to reduced or impaired effector cell function in these locations. This may explain similar observations in our study where patients with serous effusions or hepatic or CNS disease were more resistant to therapy. In the case of CNS disease the absence of local effector cells may be particularly important. It may be possible to augment host effector mechanisms by addition of cytokines such as granulocyte-macrophage colony-stimulating factor and in this way improve responses.17 The clinical observations suggest that CAMPATH-1H may be most effective in patients who present with blood and BM disease alone or in whom bulky disease has already been eradicated by conventional therapy.15 The reason for the particular sensitivity of T-prolymphocytes to CAMPATH-1H is unknown. It may be related to the high level of CD52 expression on the surface of the leukemic cells, which also has some predictive value for response.5 Specific genetic abnormalities, for example inactivation of the ATM gene,18,19 may also play a role in determining responsiveness to CAMPATH-1H therapy, although we found no correlation in our study. The majority of patients who relapsed had CD52+ T cells and
6 of these patients went on to achieve second responses. However, 2 patients who had achieved durable CRs (25 and 45 months) following a
first course of CAMPATH-1H relapsed with CD52 CAMPATH-1H is a generally well-tolerated therapy. Acute infusion-related effects were only associated with initial therapy or with dose increments and were usually controlled by premedication. Antihistamines are probably less effective than steroids, but in this study prednisolone was not used to avoid confusion over response evaluation. Use of steroids would need to be restricted to the first 1 to 2 weeks of treatment to avoid increasing the immunosuppression. Systemic side effects may also be reduced by subcutaneous administration of CAMPATH-1H. Studies in CLL suggest that this does not reduce efficacy14 although we have no data to support this in T-PLL. The dose schedule of 30 mg 3 times a week was selected following results of a phase 1 study. However, the optimal dose and dose interval are not yet clearly established and need to be further evaluated. The most significant side effect was prolonged lymphopenia associated with reactivation of viruses such as CMV and herpes and other opportunistic infections. Use of antibacterial and antiviral prophylaxis is important and should probably be continued for at least 3 months after completing therapy. Two patients developed prolonged and unexplained BM aplasia. In both cases this occurred as a relatively late complication following partial BM recovery and was not associated with a documented infection such as parvovirus. It is possible that an untested virus such as human herpesvirus 8, which has recently been implicated in posttransplant aplasia, was responsible.21 CD52 is not expressed on hemopoietic progenitors and CAMPATH-1H would not therefore be expected to cause direct toxicity to stem cells.4 Comparable degrees of aplasia have not been observed in patients with B-cell malignancies and the cause for this event and its apparent association with T-PLL is not clear. In summary, CAMPATH-1H is an effective and well-tolerated therapy in T-PLL, able to produce durable remissions in two thirds of patients. These results show a significant improvement over previous therapy and offer the hope of improved survival in the majority of patients. We would, therefore, consider CAMPATH-1H to be the first-line treatment in T-PLL. This agent is not, however, curative and other strategies such as SCT need to be further explored if the natural history of this aggressive malignancy is to be significantly altered.
We are grateful to the Ilex Corporation and Geoff Hale for supply of CAMPATH-1H, to John Swansbury for the statistical analysis, to Ricardo Morilla for flow cytometry, to Peter de Schuower for some of the PCR work, and to Stephen Devereux, Andrew Duncombe, Robin Ireland, M. Wetterwald, M. Ojeda, B. Mahe, and E. Carreras for providing patient data.
Submitted December 29, 2000; accepted May 15, 2001.
Supported by research funding from the Royal Marsden Hospital Trustees.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Claire Dearden, St George's Hospital Medical School, Cranmer Terrace, London SW17 OQT, United Kingdom; e-mail: claire.dearden{at}ccmail.stgh-tr.sthames.nhs.uk.
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Top
Abstract
Introduction
indicates dead; 
, alive.
indicates dead; 
, alive.
