2-Chlorodeoxyadenosine Treatment of Low-Grade Lymphomas By A.C. Kay, A. Saven, C.J. Carrera, D.A. Carson, D. Thurston, E. Beutler, and L.D. Piro Purpose: Because of the need to identify effective new agents in the treatment of non-Hodgkin's lymphoma and because of the high activity of the purine analog 2-chlorodeoxyadenosine (2-CdA) against chronic lymphocytic leukemia and hairy cell leukemia, a phase II trial of 2-CdA was initiated in patients with low-grade lymphocytic lymphomas. Patients and Methods: Forty patients with low-grade lymphocytic lymphomas including diffuse small lymphocytki, follicular small-cleaved, and follicular mixed histologies were enrolled onto the study. Conventional therapies had failed in all patients, and six patients had lymph node biopsies showing evidence of histologic evolution to a higher-grade lymphoma. A total of 107 courses of 2-CdA Werie administered. There were 27 males and 13 females. The median age was 59 years (range, 37 to 80 years). Patients had received a median of three prior therapies (range, one to six therapies). Results: An overall response rate of 43%was achieved,
with eight patients experiencing complete responses (CRs) and nine patients experiencing partial responses (PRs). The duration of responses ranged from 1 to greater than 33 months without maintenance therapy (median duration of response, 5 months). Histology and prior therapy history did not seem to correlate with responses. Significant toxicity was limited to bone marrow suppression; 18% of patients developed neutropenia, and 30% developed thrombocytopenia. Conclusions: This phase II trial demonstrates that 2-CdA is an effective antilymphocyte, antineoplastic agent with significant activity as a single agent in patients with recurrent or refractory low-grade lymphocytic lymphoma. Responses were achieved with an acceptable toxicity profile. Furthertrials of this agent in previously untreated patients and in combination regimens are indicated and will be developed. J Clin Oncol 10:371-377. © 1992 by American Society of Clinical Oncology.
T HE LOW-GRADE lymphocytic lymphomas are a
these diseases, we initiated a phase II trial of 2-CdA in
group of indolent B-cell neoplasms that often do not require therapy. Eventually, symptomatic adenopa-
the low-grade lymphocytic lymphomas.7
10
PATIENTS AND METHODS
thy, organ infiltration, and bone marrow involvement
may necessitate treatment. Chemotherapy with oral
Eligibility Criteria
alkylating agents and prednisone may produce objective
Patients were required to be more than 18 years of age and have a 3-month or greater life expectancy. The diagnosis of a low-grade lymphoma or a previous low-grade lymphoma with evolution to an intermediate-grade histology was confirmed at our institution. Low-grade lymphoma included the following subtypes: diffuse small lymphocytic, follicular small-cleaved, and follicular mixed lymphomas. Evolution toward a higher grade evidenced on lymph node biopsy included the following pathologic subtypes: diffuse small-cleaved, diffuse large-cell, diffuse mixed, and follicular largecell. Other entrance criteria included failure to respond to conventional therapy, the absence of prior chemotherapy or radiation therapy for at least 4 weeks, and the absence of active infection. Patients with a second malignancy were excluded. Normal hepatic and renal function were required except in patients where it could be demonstrated that lymphoma was the direct cause of the
responses in up to 65%
of previously untreated pa-
tients,12' although complete responses (CRs) are less
common than partial responses (PRs), and relapses almost always occur. Combination chemotherapy and combined chemotherapy and radiotherapy provide no
demonstrated survival advantage over single agents.3"5 Once patients develop resistance to alkylating agents, there is no standard salvage regimen. Low-grade lymphomas may evolve to higher-grade neoplasms with a poor response to available treatments, further complicating
management and conferring a worse prognosis. 2-chlorodeoxyadenosine (2-CdA) is a purine analog
that is resistant to degradation by adenosine deaminase. This deoxyadenosine congener accumulates in cells with
high deoxycytidine kinase activity and, therefore, is relatively lymphocyte-specific.
After treatment with
2-CdA, DNA strand breaks accumulate, resulting in cell death. However, the exact mechanism of action remains 6
elusive.
2-CdA has been demonstrated to kill both
resting and dividing cells, making it an ideal agent for neoplasms with a low-growth fraction, such as the
low-grade lymphocytic lymphomas. Because prior studies have documented substantial activity of 2-CdA in
chronic lymphocytic leukemia and hairy cell leukemia, and because of the need for new effective therapies in
From the Division ofHematology and Oncology andDepartmentof Molecular and Experimental Medicine, Scripps Clinic and Research Foundation,La Jolla, CA. Submitted April 8, 1991; accepted October2, 1991. Supported in part by National Institutes of Health grant no. RR00833, GM23200, and FDR-00028003, and the Sam Stein and Rose Stein CharitableTrust Fund. This is publication no. 6570-MEM from the Research Institute of Scripps Clinic, La Jolla, CA. Address reprint requests to Lawrence D. Piro, MD, Division of Hematology and Oncology, Scripps Clinic andResearch Foundation, 10666 North Torrey PinesRd, La Jolla, CA 92037 © 1992 byAmerican Society of ClinicalOncology. 0732-183X/92/1003-0020$3.00/0
Journalof Clinical Oncology, Vol 10, No 3 (March), 1992: pp 371-377
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371
372
KAY ET AL
abnormality. All patients gave informed consent and institutional review board approval was obtained.
monitored and assessed according to the Eastern Cooperative Oncology Group criteria."
PretreatmentStudies
StatisticalAnalysis
All patients underwent pretreatment evaluation with a medical history; physical examination; computed tomography (CT) of the chest, abdomen, and pelvis; bone marrow aspiration and biopsy; complete blood cell count; serum immunoelectrophoresis; and chemistry panel to assess liver and renal function.
Statistical analyses of patient responses were performed using the X2 method, and Fisher's exact test one-sided P values are reported. The level of significance was a P value less than .05.
RESULTS
Posttreatment Patients were routinely reevaluated after two cycles of therapy with repeat CT scans of the involved areas and, if indicated, a bone marrow biopsy. If disease progression was suspected before completion of two cycles, reevaluation was performed earlier. If response was documented, patients were restaged using the same tests once maximal response was achieved.
Study Population Forty consecutive patients with a diagnosis of lowgrade lymphoma or a prior diagnosis of low-grade lymphoma with evolution to a higher grade were evaluated at the Scripps Clinic between January 1987 and June 1990. In all patients, the lymphoma was recurrent
Drug Therapy
or refractory to one or more conventional treatment
2-CdA was synthesized and purified as described"12 and was supplied to the pharmacy as a 0.1% solution (1 mg/mL) of pyrogen-free 2-CdA in sterile 0.9% sodium chloride. 2-CdA was administered at a dose of 0.1 mg/kg/d by continuous infusion for 7 consecutive days. Cycles of treatment were started every 5 weeks unless grade 3 or 4 myelosuppression occurred. Treatment was resumed when counts reached 75% of pretreatment values. If response was documented, patients were treated until maximal response or prohibitive toxicity; then treatment was discontinued, and the patients were observed. If no response or progressive disease was documented after two cycles, treatment was discontinued.
modalities. There were three patients with follicular mixed histology, 17 patients with follicular small-cleaved
Response Criteria A CR was defined as absence of disease on physical exam; CT scan of the chest, abdomen, and pelvis; and, if previously involved, bone marrow biopsy. The posttreatment bone marrow must have less than 30% lymphocytes and no evidence of abnormal lymphoid infiltration. All lymph nodes must have returned to normal size; splenomegaly and/or hepatomegaly must also have fully resolved on CT scan. B symptoms, if present, must have abated. A PR was defined as reduction in all involved areas of disease by at least 50%. Any response less than that sufficient to qualify as a PR was no response (NR). Progressive disease was defined as a > 25% increase in measurable disease. Toxicity Criteria Hematologic toxicity was evaluated according to an adaptation of the National Cancer Institute Guidelines for Chronic Lymphocytic Leukemia" listed in Table 1. All other toxic effects were Table 1. Grading Scale for Hematologic Toxicity Grade
Decrease From Pretreatment Value (%)
Platelets
Hemoglobin
Neutrophils
0-10 11-24 25-49 50-74 >75
0 1 2 3 4
0 1 2 3 4
0 1 2 3 4
histology, and 14 patients with diffuse small lymphocytic histology. Twenty-seven males and 13 females were enrolled, ranging in age from 37 to 80 years of age (median age, 59 years). Duration of disease ranged from 3 months to 10 years (median, 3V2 years). Twenty-nine patients were refractory to chemotherapy, 10 were recurrent after prior therapy, and one patient had residual disease despite six cycles of treatment with methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD). The number of prior treatment regimens ranged from one to six (median, three). Thirty-one patients had stage IV disease, seven had stage III disease, one had stage II disease, and one had stage I disease involving the skin. Nine patients had B symptoms. In 36 patients the diagnosis was originally established on lymph node biopsy, in one each by splenectomy and pleural biopsy, and in two patients by bone marrow biopsy alone. Six patients had evidence of evolution to an intermediate-grade histologic subtype, and 34 had low-grade lymphoma at the time 2-CdA was administered. Two patients evolved to an intermediate-grade lymphoma after 2-CdA was administered. One of these patients developed a diffuse, mixed B-cell lymphoma while the other developed a T-cell neoplasm. A monoclonal gammopathy was detected in the serum of 12 of the patients. Twenty-two patients were hypogammaglobulinemic. Ten patients had a peripheral-blood lymphocytosis associated with low-grade lymphoma. All such cases were reviewed by Dr Robert Lukes and believed to have morphology consistent with leukemic phase of lymphoma and not chronic lymphocytic leukemia. Most were CD5-negative on flow-cytometric analysis.
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373
2-CDA TREATMENT OF LYMPHOMAS
All patients had normal renal function. Pretreatment liver function tests were normal in all but one patient who had a mild cholestatic picture secondary to obstructive adenopathy. One hundred seven cycles of 2-CdA were administered to 40 patients. The median number of cycles was three (range, one to six cycles). Responses to Therapy Of 40 patients, 17 (43%) experienced responses. There were eight CRs (20%) and nine PRs (23%). Tables 2 and 3 summarize patient responses and their histologic subtypes. After achieving maximal response, the patients were observed without receiving further therapy. The duration of CRs ranged from 1 to greater than 33 months (median, 6 months). The duration of PRs ranged from 3 to 6 months. Of the eight complete responders, four remain in remission at 33, 29, 12, and 2 months; four have relapsed. Two patients who relapsed before 6 months after documented CRs did not respond to re-treatment with 2-CdA. The other two patients, who both relapsed at 6 months, have been observed and have not required further therapeutic intervention. Of the nine partial responders, three remain stable at 6, 5, and 5 months posttreatment; six have had disease progression. One patient developed a new T-cell neoplasm after achieving a PR of 3 months' duration from the B-cell lymphoma. Four patients progressed after 4 months, and one relapsed at 6 months posttreatment. The patient who relapsed at 6 months developed an associated autoimmune hemolytic anemia and was retreated with an additional cycle of 2-CdA therapy. The Table 2. Summary of Results in Low-Grade Lymphoma Patients Diagnosis at Time of Treatment Follicular small-cleaved
Follicular mixed
Diffuse small lymphocytic
Stage
IlIA IIIA IVA IVA IVA IVB IVB IIIA IVA IVB IA
IlIA IVA IVA IVA IVB IVB
No. of Patients
2 1
3 1
6 2 2 1 1 1
1 1 1 1 7 1 2
Response/ Duration (months) PR/4, 4 NR CR/33+, 6,2+ PR/5+ NR PR/5+, 3 NR CR/1 CR/2 NR CR/12+ PR/4 CR/6+ PR/6 NR CR/6 NR
Table 3. Summary of Results in Patients With Disease Evolution Diagnosis at Time of Treatment
Stage
No. of Patients
Response/ Duration (months)
IIIA
1
CR/29+
IVA
1
NR
IVA IIIA
1 1
PR/4 NR
IVA
1
NR
IIA
1
NR
Follicular large-cell from follicular mixed Follicular and diffuse large-cell from follicular small-cleaved Follicular large-cell from follicular smallcleaved Diffuse mixed from follicular mixed Diffuse large-cell from diffuse small lymphocytic Diffuse large-cell from diffuse small lymphocytic
hemolytic anemia resolved, allowing danazol and prednisone to be discontinued, and the lymphoma remained stable for 6 months after the second treatment course but has subsequently progressed without a return of hemolysis. Serum immunoglobulin (Ig) levels remained stable throughout treatment and follow-up in all patients. Four patients who responded had a pretreatment paraprotein detectable, which did not change after treatment response. T-cell subsets are being analyzed and will be reported in future publications. Analyzing the responses obtained according to follicular or diffuse histology, the follicular subtypes appear to be more responsive to therapy. Twelve responses were seen of the 24 (50%) patients with follicular subtypes, whereas only five of 16 (31%) patients with diffuse subtypes responded. Despite these differences in response, the P value (.36) was not significant. These results are summarized in Table 4. The responses of patients to 2-CdA were examined in comparison to their prior responses to chemotherapy. Of the 17 patients who responded to 2-CdA, 12 were refractory to prior chemotherapy, four had relapsed disease after prior treatment to which they had responded, and one had residual disease after chemotherapy. Table 5 is a summary of the 2-CdA-responsive Table 4. Response by Histologic Subtype Response (CRs + PRs)
NR
Histologic Subtype
No.
%
Follicular* Diffuse* With evolu tiont Without evolutiont Overall
12/24 5/16 2/6 15/34 17/40
50 31 33 44 43
%
No.
12/2 11/1 4/6 19/3 23/4
4 6 4 0
50 69 67 55 57
*Fisher's exact test one-sided P value = .36 (not statistically significant). tFisher's exact test one-sided P value = .49 (not statistically significant).
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374
KAY ET AL Table 5. Patient Characteristics
Diagnosis/Stage Diffuse small lymphocytic/IAE* Diffuse small lymphocytic/IlIIA Diffuse small lymphocytic/IVA Diffuse small lymphocytic/IVA Diffuse small lymphocytic/IVB Follicular small-cleaved/lllA Follicular small-cleaved/IlIA Follicular small-cleaved/IVA Follicular small-cleaved/IVA Follicular small-cleaved/IVA Follicular smoll-cleaved/IVA Follicular small-cleaved/IVB Follicular small-cleaved/IVB Follicular large-cell evolved from follicular small-cleaved/IVA Follicular mixed/IIIA Follicular mixed/IVA Follicular large-cell evolved from follicular mixed/iliA
Status at Time of 2-CdA
No. of Cycles of 2-CdA
2-CdA Response/ Duration (months)
PR (12) NR PR (12) PR (3) PR NR PR (12) NR PR (6) NR PR (48) PR (3) PR (3)
Ref Ref Ref Ref Ref Ref Ref Ref Rec Ref Ref Rec Res
2 2 4, 1 4 2 3 5 3 2 2 3 5 2
CR/12+ PR/4 PR/6 PR/6+ CR/6 PR/4 PR/4 CR/33+ CR/6 CR/2+ PR/5+ PR/3 PR/5+
1,3, 6 1,2, 3, 6 1, 3, 5
PR (8) PR (5) NR
Rec Ref Ref
2 2, 3 3
PR/4 CR/1 CR/2
1,4, 8, 12
CR (30) (16) (3)
Rec
I
Prior Treatment 1,2, 1 1,2 1,9, 1,2, 1,2 1,2, 3 1,2, 7 3 1,2, 5
6
10, 13 11 3, 4, 6 3, 4, 6
6
Prior Response (months)
CR/29+
Abbreviations: 1, single-alkylator Cytoxan (cyclophosphamide; Bristol-Myers Squibb Co, Evansville, IN), Leukeran (leucovorin; Burroughs Wellcome Co, Research Triangle Park, NC), chlorambucil, or Alkeran (melphalan; Burroughs Wellcome Co); 2, corticosteroids; 3, cyclophosphamide, vincristine, and prednisone (CVP); 4, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); 5, m-BACOD; 6, radiation therapy; 7, interferon alfa; 8, cyclophosphamide, mechlorethamine, vincristine, procarbazine, and prednisone (C-MOPP); 9, Cytoxan, etoposide (VP16), procarbazine, and prednisone; 10, fludarabine; 11, Leukeran, vincristine, and prednisone; 12, bleomycin, lomustine, VP16, procarbazine, and prednisone (B-CEPP); 13, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), VP16, methotrexate, and prednisone; Ref, refractory to prior therapy; Rec, recurrent after therapy; Res, residual disease after therapy. *Skin involvement.
patients and their prior therapies and responses. Analysis of the responses to 2-CdA compared with prior chemotherapy responsiveness showed that 12 (41%) of the 29 refractory patients and four (40%) of the 10 patients with recurrent disease responded. The differences observed were not significant (Fisher's exact test one-sided P value = .62). The responding patients received two to five cycles of 2-CdA (median, two cycles). CRs occurred in five patients who received two cycles and three patients who received three cycles. PRs were observed in three patients who received two cycles, two patients who received three cycles, two patients who received four cycles, and two patients who received five cycles. Benefit was demonstrated after two or three cycles of 2-CdA, but patients were continued on therapy in an attempt to achieve a CR. The two patients who received five cycles were discontinued from therapy because of lack of further response, not because of drug toxicity. Toxicity
As with other phase II clinical trials of 2-CdA, little nonhematologic toxicity was experienced at a dose of 0.1
mg/kg/d. No patients experienced nausea, vomiting, mucositis, neurologic symptoms, or alopecia. No drug-related renal or hepatic toxicity was encountered. One patient had elevated creatinine levels during therapy. This patient had a pretreatment creatinine level of 1.4 mg/dL, which rose transiently to 2.4 mg/dL during the course of uric acid nephropathy and returned to pretreatment levels. Bone Marrow Suppression
Grade 3 or 4 neutropenia was experienced by seven of the 40 patients (18%). The nadir of neutrophil counts occurred between 7 and 14 days posttherapy. Recovery to baseline values usually occurred by 28 days posttherapy. Of the patients who experienced neutropenia, three of seven patients had documented sepsis. Two patients had Pseudomonas aeruginosa pneumonitis with sepsis, and the third had a Staphylococcus aureus intravenous
site infection. Grade 3 or 4 thrombocytopenia was seen in 12 of 40 patients (30%). Only one patient's platelet count fell below 20,000/pL. No life-threatening bleeding problems occurred. The nadir of the platelet count occurred
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375
2-CDA TREATMENT OF LYMPHOMAS
between 7 and 21 days posttherapy. Recovery of platelet counts occurred between 28 days and 42 days posttherapy. Only seven of the 107 cycles of 2-CdA were delayed because of cytopenia. We found evidence of cumulative myelosuppression with 2-CdA therapy. WBC counts fell on average to 95% (+ 11% SE) of the pretreatment value after two cycles of 2-CdA, 74% (± 6% SE) after three cycles, and 54% (± 4% SE) with four cycles of therapy. (Patients with a lymphomatous leukemic phase were excluded from analysis of WBC counts but not excluded from absolute neutrophil count analysis.) Absolute neutrophil counts were on average maintained after two or three cycles of treatment. On average, the mean granulocyte count actually improved with subsequent cycles of 2-CdA therapy. After two cycles, the mean granulocyte count rose to 130% of normal (± 24% SE) and, after three cycles, was 114% of normal (± 29% SE). The platelet counts fell to 80% (± 19% SE) of their pretreatment levels, with either two or three cycles of 2-CdA. No further decrement in the platelet count was observed beyond that observed after three cycles. Long-term follow-up of two patients who remain in CR after 33 and 29 months shows these patients to have normal complete blood cell counts with normal absolute neutrophil counts and normal absolute lymphocyte counts. Infectious Complications Five of 40 patients had documented bacteremias. Three of the five patients experienced gram-negative sepsis within 1 month of receiving 2-CdA therapy. In two of these three patients, P aeruginosa was identified. The third patient had Escherichiacoli isolated and was found to have appendicitis with perforation. Two of 40 patients experienced intravenous site infections. One patient had Serratiamarcescens infection of his central venous catheter, and in the second patient, a peripheral intravenous site infection was complicated by S aureus bacteremia. One patient experienced acute cytomegalovirus (CMV) pneumonitis, hepatitis, and, presumptively, encephalitis concomitant with a fulminant relapse and evolution of his disease 6 months after treatment. The diagnosis of acute CMV infection was made by examination of IgG titers. The patient's CMV IgG titer had risen to 1:23,768. The patient's liver enzymes were elevated with a hepatocellular pattern, alkaline phosphatase level of 60 U/L (normal, 35 to 108 U/L), total bilirubin level of 2.8 mg/dL (normal, 0.0 to 1.5 mg/dL), SGOT level of 321 U/L (normal, 9 to 50 U/L), and SGPT level of 456 U/L (normal, 8 to 62 U/L). Hepatitis A and B serologies
were negative. The patient had a diffuse interstitial pneumonitis on chest x-ray and was febrile to 39 0 C on multiple occasions. He was obtunded; no focal neurologic signs were present. Blood and urine cultures were negative for bacterial and fungal growth. CSF examination was normal except for an elevation of the protein at 90 mg/dL (normal, 15 to 45 mg/dL). This clinical pattern occurred 6 months after treatment with 2-CdA and in association with relapse. Thus, there is no evidence to suggest a CNS effect of the drug. Oral herpes simplex infection occurred in two patients, and dermatomal herpes zoster infection was seen in one patient during 2-CdA treatment. No patients developed disseminated herpes simplex or zoster infections. One patient who was receiving high doses of corticosteroids in addition to 2-CdA for autoimmune hemolytic anemia experienced recurrent pneumonias. Open-lung biopsy yielded the diagnosis of a granulomatous process that revealed no growth of mycobacterial or fungal cultures. However, the patient has responded to empiric antituberculous therapy. DISCUSSION The low-grade lymphocytic lymphomas are often indolent diseases, and patients may survive many years without treatment. Except in follicular mixed lymphomas, the survival of patients with low-grade lymphomas has not been convincingly changed by treatment. Although alkylating agents, prednisone, and combination chemotherapy can have a salutary effect on the symptoms and manifestations of the disease, the responses are often incomplete, and eventual relapses are the rule. This may be due in part to the fact that the low-grade lymphomas have a low growth fraction such that the majority of the malignant cells in these patients are nondividing lymphocytes. Despite excellent clinical responses to therapy, malignant lymphocytes may become resistant to the drugs or may be protected from their effects because the cells are not cycling. These residual cells result in relapse and are the reason new drugs are needed to treat these diseases more effectively. 2-CdA has been shown to achieve cytoreduction in advanced indolent B-cell neoplasms. This may be due in part to its ability to kill lymphocytes independently of cell division.' Consistent with our observations with chronic lymphocytic leukemia and hairy cell leukemia, this study has demonstrated a significant response rate with this single agent in the treatment of recurrent or refractory low-grade lymphomas. Especially important is the fact that eight of the 17 patients who responded
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KAY ET AL
376 experienced CRs, an uncommon observation with a single agent in extensively pretreated patients. Part of the difficulty inherent in treating patients with low-grade lymphomas is that they often evolve to highergrade histologies, conferring a worse prognosis. Such an evolution was documented in this study in six patients before therapy and two patients after therapy. Interestingly, analysis of our data according to presence or absence of histologic evolution showed no significant response differences in the groups: two of six patients responded in the group with evolution, and 14 of 34 responded in the group without evolution. The spectrum of toxicity of 2-CdA in this trial has been similar to that seen in studies of other low-grade B-cell malignancies with an absence of traditional chemotherapy side effects. The dose-limiting toxicity is myelosuppression, which occurs at an acceptable incidence in the doses used in this and other phase II trials of this agent in lymphoid malignancies. The infections seen were those that typically occur in lymphoma patients and with conventional chemotherapy. Cytopenias occurred in one third of the patients. Hematologic toxicity was observed principally in those patients who had been heavily pretreated and had extensive bone marrow involvement by their disease. Myleosuppression was cumulative, but long-term follow-up of two disease-free patients showed no abnormalities. However, there has been some experience with cumulative myelosuppression observed in patients with normal bone marrows. Four patients with multiple sclerosis were treated with the same dosage and schedule of 2-CdA as the lymphoma patients. These patients have manifested minimal suppression of their granulocyte, platelet, and absolute lymphocyte counts for up to 6 months posttreatment. While aggressive treatment strategies are emerging in
the treatment of certain low-grade lymphomas, including bone marrow transplantation, these techniques are still limited by the difficulties in achieving total or near-total cytoreduction with the available agents. It is clear that new agents are needed to accomplish this goal. This study of 2-CdA indicates that it may be such an effective agent. Fludarabine phosphate, another nucleoside with similar response rates in lymphocytic lymphoma,'. 15 6 will also be effective in the management of low-grade lymphomas. However, fludarabine is limited in its application for dose-intensive therapy because of dose-limiting CNS toxicity. 2-CdA is an agent that may be able to be dose-escalated in this setting. This agent has been given to 14 patients at twice the dosage used here with no organ toxicity except myelosuppression. Two of these 14 patients received two cycles of 0.2 mg/kg/d for 7 days. However, when given at considerably higher doses (0.4 mg/kg/d for 7 days followed by 0.5 mg/kg/d for 7 days sequentially) in conjunction with total body irradiation and cyclophosphamide (60 mg/kg for two doses), nephrotoxicity and neurotoxicity were observed.1 7 Whether or not the toxicity seen at the high doses was due to the drug alone or its combination with cyclophosphamide and total body irradiation is not known. These observations, however, suggest that 2-CdA may have a role in dose-intensive approaches. Further work in defining the ideal dose ranges for this application will be required. ACKNOWLEDGMENT We thank Dr Robert Lukes for his expertise in reviewing the biopsy materials. We acknowledge Drs Charles Kossman, Howard Davidson, Richard Anderson, the staff of the General Clinical Research Center, and Patricia A. Morin, RN, for their assistance in this project.
REFERENCES 1. Portlock CS: Management of the indolent non-Hodgkin's lymphomas. Semin Oncol 7:292-301, 1980 2. Portlock CS: Management of the low-grade non-Hodgkin's lymphomas. Semin Oncol 17:51-59, 1990 3. Portlock CS, Rosenberg SA: Chemotherapy of the nonHodgkin's lymphomas: The Stanford experience. Cancer Treat Rep 61:1049-1055, 1977 4. Kennedy BJ, Bloomfield CD, Kiang DT, et al: Combination versus successive single agent chemotherapy in lymphocytic lymphoma. Cancer 41:23-28, 1978 5. Ezdinli EZ, Costello WG, Silverstein MN, et al: Moderate versus intensive chemotherapy of prognostically favorable nonHodgkin's lymphoma. Cancer 46:29-33, 1980 6. Seto S, Carrera CJ, Kubota M, et al: Mechanism of deoxyadenosine and 2-chlorodeoxyadenosine toxicity to nondividing human lymphocytes. J Clin Invest 75:377-383, 1985
7. Piro LD, Carrera CJ, Beutler E, et al: 2-Chlorodeoxyadenosine: An effective new agent for the treatment of chronic lymphocytic leukemia. Blood 72:1069-1073, 1988 8. Piro LD, Carrera CJ, Carson DA, et al: Lasting remissions in hairy-cell leukemia induced by a single infusion of 2-chlorodeoxyadenosine. N Engl J Med 322:1117-1121, 1990 9. Kay AC, Carrera CJ, Carson DA, et al: Phase II trial of 2-chlorodeoxyadenosine in low-grade lymphoma. Blood 74:121A, 1989 (abstr) 10. Carson DA, Wasson DB, Beutler E: Antileukemic and immunosuppressive activity of 2-chloro-2'-deoxyadenosine. Proc Natl Acad Sci USA 81:2232-2236, 1984 11. Carson DA, Wasson DB, Taetle R, et al: Specific toxicity of 2-chlorodeoxyadenosine toward resting and proliferating human lymphocytes. Blood 62:737-743, 1983 12. Carson DA, Wasson DB, Kaye J, et al: Deoxycytidine
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377
2-CDA TREATMENT OF LYMPHOMAS kinase-mediated toxicity of deoxyadenosine analogs toward malignant human lymphoblasts in vitro and toward murine L1210 leukemia in vivo. Proc Natl Acad Sci USA 77:6865-6869, 1980 13. Cheson BD, Bennett JM, Rai KR, et al: Guidelines for clinical protocols for chronic lymphocytic leukemia: Recommendations of the National Cancer Institute-sponsored Working Group. Am J Hematol 29:152-163, 1988 14. Oken MM, Creech RH, Tormey DC, et al: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982
15. Redman J, Cabanillas F, McLaughlin P, et al: Fludarabine phosphate-A new agent with major activity in low-grade lymphoma. Proc Am Assoc Cancer Res 29:211, 1988 (abstr) 16. Kantarjian HM, Alexanian R, Koller CA, et al: Fludarabine therapy in macroglobulinemic lymphoma. Blood 75:1928-1931, 1990 17. Beutler E, Piro LD, Saven A, et al: 2-chlorodeoxyadenosine (2-CdA). A potent chemotherapeutic and immunosuppressive nucleotide. Leukemia and Lymphoma 5:1-8, 1991
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with eight patients experiencing complete responses (CRs) and nine patients experiencing partial responses (PRs). The duration of responses ranged from 1 to greater than 33 months without maintenance therapy (median duration of response, 5 months). Histology and prior therapy history did not seem to correlate with responses. Significant toxicity was limited to bone marrow suppression; 18% of patients developed neutropenia, and 30% developed thrombocytopenia. Conclusions: This phase II trial demonstrates that 2-CdA is an effective antilymphocyte, antineoplastic agent with significant activity as a single agent in patients with recurrent or refractory low-grade lymphocytic lymphoma. Responses were achieved with an acceptable toxicity profile. Furthertrials of this agent in previously untreated patients and in combination regimens are indicated and will be developed. J Clin Oncol 10:371-377. © 1992 by American Society of Clinical Oncology.
T HE LOW-GRADE lymphocytic lymphomas are a
these diseases, we initiated a phase II trial of 2-CdA in
group of indolent B-cell neoplasms that often do not require therapy. Eventually, symptomatic adenopa-
the low-grade lymphocytic lymphomas.7
10
PATIENTS AND METHODS
thy, organ infiltration, and bone marrow involvement
may necessitate treatment. Chemotherapy with oral
Eligibility Criteria
alkylating agents and prednisone may produce objective
Patients were required to be more than 18 years of age and have a 3-month or greater life expectancy. The diagnosis of a low-grade lymphoma or a previous low-grade lymphoma with evolution to an intermediate-grade histology was confirmed at our institution. Low-grade lymphoma included the following subtypes: diffuse small lymphocytic, follicular small-cleaved, and follicular mixed lymphomas. Evolution toward a higher grade evidenced on lymph node biopsy included the following pathologic subtypes: diffuse small-cleaved, diffuse large-cell, diffuse mixed, and follicular largecell. Other entrance criteria included failure to respond to conventional therapy, the absence of prior chemotherapy or radiation therapy for at least 4 weeks, and the absence of active infection. Patients with a second malignancy were excluded. Normal hepatic and renal function were required except in patients where it could be demonstrated that lymphoma was the direct cause of the
responses in up to 65%
of previously untreated pa-
tients,12' although complete responses (CRs) are less
common than partial responses (PRs), and relapses almost always occur. Combination chemotherapy and combined chemotherapy and radiotherapy provide no
demonstrated survival advantage over single agents.3"5 Once patients develop resistance to alkylating agents, there is no standard salvage regimen. Low-grade lymphomas may evolve to higher-grade neoplasms with a poor response to available treatments, further complicating
management and conferring a worse prognosis. 2-chlorodeoxyadenosine (2-CdA) is a purine analog
that is resistant to degradation by adenosine deaminase. This deoxyadenosine congener accumulates in cells with
high deoxycytidine kinase activity and, therefore, is relatively lymphocyte-specific.
After treatment with
2-CdA, DNA strand breaks accumulate, resulting in cell death. However, the exact mechanism of action remains 6
elusive.
2-CdA has been demonstrated to kill both
resting and dividing cells, making it an ideal agent for neoplasms with a low-growth fraction, such as the
low-grade lymphocytic lymphomas. Because prior studies have documented substantial activity of 2-CdA in
chronic lymphocytic leukemia and hairy cell leukemia, and because of the need for new effective therapies in
From the Division ofHematology and Oncology andDepartmentof Molecular and Experimental Medicine, Scripps Clinic and Research Foundation,La Jolla, CA. Submitted April 8, 1991; accepted October2, 1991. Supported in part by National Institutes of Health grant no. RR00833, GM23200, and FDR-00028003, and the Sam Stein and Rose Stein CharitableTrust Fund. This is publication no. 6570-MEM from the Research Institute of Scripps Clinic, La Jolla, CA. Address reprint requests to Lawrence D. Piro, MD, Division of Hematology and Oncology, Scripps Clinic andResearch Foundation, 10666 North Torrey PinesRd, La Jolla, CA 92037 © 1992 byAmerican Society of ClinicalOncology. 0732-183X/92/1003-0020$3.00/0
Journalof Clinical Oncology, Vol 10, No 3 (March), 1992: pp 371-377
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371
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KAY ET AL
abnormality. All patients gave informed consent and institutional review board approval was obtained.
monitored and assessed according to the Eastern Cooperative Oncology Group criteria."
PretreatmentStudies
StatisticalAnalysis
All patients underwent pretreatment evaluation with a medical history; physical examination; computed tomography (CT) of the chest, abdomen, and pelvis; bone marrow aspiration and biopsy; complete blood cell count; serum immunoelectrophoresis; and chemistry panel to assess liver and renal function.
Statistical analyses of patient responses were performed using the X2 method, and Fisher's exact test one-sided P values are reported. The level of significance was a P value less than .05.
RESULTS
Posttreatment Patients were routinely reevaluated after two cycles of therapy with repeat CT scans of the involved areas and, if indicated, a bone marrow biopsy. If disease progression was suspected before completion of two cycles, reevaluation was performed earlier. If response was documented, patients were restaged using the same tests once maximal response was achieved.
Study Population Forty consecutive patients with a diagnosis of lowgrade lymphoma or a prior diagnosis of low-grade lymphoma with evolution to a higher grade were evaluated at the Scripps Clinic between January 1987 and June 1990. In all patients, the lymphoma was recurrent
Drug Therapy
or refractory to one or more conventional treatment
2-CdA was synthesized and purified as described"12 and was supplied to the pharmacy as a 0.1% solution (1 mg/mL) of pyrogen-free 2-CdA in sterile 0.9% sodium chloride. 2-CdA was administered at a dose of 0.1 mg/kg/d by continuous infusion for 7 consecutive days. Cycles of treatment were started every 5 weeks unless grade 3 or 4 myelosuppression occurred. Treatment was resumed when counts reached 75% of pretreatment values. If response was documented, patients were treated until maximal response or prohibitive toxicity; then treatment was discontinued, and the patients were observed. If no response or progressive disease was documented after two cycles, treatment was discontinued.
modalities. There were three patients with follicular mixed histology, 17 patients with follicular small-cleaved
Response Criteria A CR was defined as absence of disease on physical exam; CT scan of the chest, abdomen, and pelvis; and, if previously involved, bone marrow biopsy. The posttreatment bone marrow must have less than 30% lymphocytes and no evidence of abnormal lymphoid infiltration. All lymph nodes must have returned to normal size; splenomegaly and/or hepatomegaly must also have fully resolved on CT scan. B symptoms, if present, must have abated. A PR was defined as reduction in all involved areas of disease by at least 50%. Any response less than that sufficient to qualify as a PR was no response (NR). Progressive disease was defined as a > 25% increase in measurable disease. Toxicity Criteria Hematologic toxicity was evaluated according to an adaptation of the National Cancer Institute Guidelines for Chronic Lymphocytic Leukemia" listed in Table 1. All other toxic effects were Table 1. Grading Scale for Hematologic Toxicity Grade
Decrease From Pretreatment Value (%)
Platelets
Hemoglobin
Neutrophils
0-10 11-24 25-49 50-74 >75
0 1 2 3 4
0 1 2 3 4
0 1 2 3 4
histology, and 14 patients with diffuse small lymphocytic histology. Twenty-seven males and 13 females were enrolled, ranging in age from 37 to 80 years of age (median age, 59 years). Duration of disease ranged from 3 months to 10 years (median, 3V2 years). Twenty-nine patients were refractory to chemotherapy, 10 were recurrent after prior therapy, and one patient had residual disease despite six cycles of treatment with methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD). The number of prior treatment regimens ranged from one to six (median, three). Thirty-one patients had stage IV disease, seven had stage III disease, one had stage II disease, and one had stage I disease involving the skin. Nine patients had B symptoms. In 36 patients the diagnosis was originally established on lymph node biopsy, in one each by splenectomy and pleural biopsy, and in two patients by bone marrow biopsy alone. Six patients had evidence of evolution to an intermediate-grade histologic subtype, and 34 had low-grade lymphoma at the time 2-CdA was administered. Two patients evolved to an intermediate-grade lymphoma after 2-CdA was administered. One of these patients developed a diffuse, mixed B-cell lymphoma while the other developed a T-cell neoplasm. A monoclonal gammopathy was detected in the serum of 12 of the patients. Twenty-two patients were hypogammaglobulinemic. Ten patients had a peripheral-blood lymphocytosis associated with low-grade lymphoma. All such cases were reviewed by Dr Robert Lukes and believed to have morphology consistent with leukemic phase of lymphoma and not chronic lymphocytic leukemia. Most were CD5-negative on flow-cytometric analysis.
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373
2-CDA TREATMENT OF LYMPHOMAS
All patients had normal renal function. Pretreatment liver function tests were normal in all but one patient who had a mild cholestatic picture secondary to obstructive adenopathy. One hundred seven cycles of 2-CdA were administered to 40 patients. The median number of cycles was three (range, one to six cycles). Responses to Therapy Of 40 patients, 17 (43%) experienced responses. There were eight CRs (20%) and nine PRs (23%). Tables 2 and 3 summarize patient responses and their histologic subtypes. After achieving maximal response, the patients were observed without receiving further therapy. The duration of CRs ranged from 1 to greater than 33 months (median, 6 months). The duration of PRs ranged from 3 to 6 months. Of the eight complete responders, four remain in remission at 33, 29, 12, and 2 months; four have relapsed. Two patients who relapsed before 6 months after documented CRs did not respond to re-treatment with 2-CdA. The other two patients, who both relapsed at 6 months, have been observed and have not required further therapeutic intervention. Of the nine partial responders, three remain stable at 6, 5, and 5 months posttreatment; six have had disease progression. One patient developed a new T-cell neoplasm after achieving a PR of 3 months' duration from the B-cell lymphoma. Four patients progressed after 4 months, and one relapsed at 6 months posttreatment. The patient who relapsed at 6 months developed an associated autoimmune hemolytic anemia and was retreated with an additional cycle of 2-CdA therapy. The Table 2. Summary of Results in Low-Grade Lymphoma Patients Diagnosis at Time of Treatment Follicular small-cleaved
Follicular mixed
Diffuse small lymphocytic
Stage
IlIA IIIA IVA IVA IVA IVB IVB IIIA IVA IVB IA
IlIA IVA IVA IVA IVB IVB
No. of Patients
2 1
3 1
6 2 2 1 1 1
1 1 1 1 7 1 2
Response/ Duration (months) PR/4, 4 NR CR/33+, 6,2+ PR/5+ NR PR/5+, 3 NR CR/1 CR/2 NR CR/12+ PR/4 CR/6+ PR/6 NR CR/6 NR
Table 3. Summary of Results in Patients With Disease Evolution Diagnosis at Time of Treatment
Stage
No. of Patients
Response/ Duration (months)
IIIA
1
CR/29+
IVA
1
NR
IVA IIIA
1 1
PR/4 NR
IVA
1
NR
IIA
1
NR
Follicular large-cell from follicular mixed Follicular and diffuse large-cell from follicular small-cleaved Follicular large-cell from follicular smallcleaved Diffuse mixed from follicular mixed Diffuse large-cell from diffuse small lymphocytic Diffuse large-cell from diffuse small lymphocytic
hemolytic anemia resolved, allowing danazol and prednisone to be discontinued, and the lymphoma remained stable for 6 months after the second treatment course but has subsequently progressed without a return of hemolysis. Serum immunoglobulin (Ig) levels remained stable throughout treatment and follow-up in all patients. Four patients who responded had a pretreatment paraprotein detectable, which did not change after treatment response. T-cell subsets are being analyzed and will be reported in future publications. Analyzing the responses obtained according to follicular or diffuse histology, the follicular subtypes appear to be more responsive to therapy. Twelve responses were seen of the 24 (50%) patients with follicular subtypes, whereas only five of 16 (31%) patients with diffuse subtypes responded. Despite these differences in response, the P value (.36) was not significant. These results are summarized in Table 4. The responses of patients to 2-CdA were examined in comparison to their prior responses to chemotherapy. Of the 17 patients who responded to 2-CdA, 12 were refractory to prior chemotherapy, four had relapsed disease after prior treatment to which they had responded, and one had residual disease after chemotherapy. Table 5 is a summary of the 2-CdA-responsive Table 4. Response by Histologic Subtype Response (CRs + PRs)
NR
Histologic Subtype
No.
%
Follicular* Diffuse* With evolu tiont Without evolutiont Overall
12/24 5/16 2/6 15/34 17/40
50 31 33 44 43
%
No.
12/2 11/1 4/6 19/3 23/4
4 6 4 0
50 69 67 55 57
*Fisher's exact test one-sided P value = .36 (not statistically significant). tFisher's exact test one-sided P value = .49 (not statistically significant).
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374
KAY ET AL Table 5. Patient Characteristics
Diagnosis/Stage Diffuse small lymphocytic/IAE* Diffuse small lymphocytic/IlIIA Diffuse small lymphocytic/IVA Diffuse small lymphocytic/IVA Diffuse small lymphocytic/IVB Follicular small-cleaved/lllA Follicular small-cleaved/IlIA Follicular small-cleaved/IVA Follicular small-cleaved/IVA Follicular small-cleaved/IVA Follicular smoll-cleaved/IVA Follicular small-cleaved/IVB Follicular small-cleaved/IVB Follicular large-cell evolved from follicular small-cleaved/IVA Follicular mixed/IIIA Follicular mixed/IVA Follicular large-cell evolved from follicular mixed/iliA
Status at Time of 2-CdA
No. of Cycles of 2-CdA
2-CdA Response/ Duration (months)
PR (12) NR PR (12) PR (3) PR NR PR (12) NR PR (6) NR PR (48) PR (3) PR (3)
Ref Ref Ref Ref Ref Ref Ref Ref Rec Ref Ref Rec Res
2 2 4, 1 4 2 3 5 3 2 2 3 5 2
CR/12+ PR/4 PR/6 PR/6+ CR/6 PR/4 PR/4 CR/33+ CR/6 CR/2+ PR/5+ PR/3 PR/5+
1,3, 6 1,2, 3, 6 1, 3, 5
PR (8) PR (5) NR
Rec Ref Ref
2 2, 3 3
PR/4 CR/1 CR/2
1,4, 8, 12
CR (30) (16) (3)
Rec
I
Prior Treatment 1,2, 1 1,2 1,9, 1,2, 1,2 1,2, 3 1,2, 7 3 1,2, 5
6
10, 13 11 3, 4, 6 3, 4, 6
6
Prior Response (months)
CR/29+
Abbreviations: 1, single-alkylator Cytoxan (cyclophosphamide; Bristol-Myers Squibb Co, Evansville, IN), Leukeran (leucovorin; Burroughs Wellcome Co, Research Triangle Park, NC), chlorambucil, or Alkeran (melphalan; Burroughs Wellcome Co); 2, corticosteroids; 3, cyclophosphamide, vincristine, and prednisone (CVP); 4, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); 5, m-BACOD; 6, radiation therapy; 7, interferon alfa; 8, cyclophosphamide, mechlorethamine, vincristine, procarbazine, and prednisone (C-MOPP); 9, Cytoxan, etoposide (VP16), procarbazine, and prednisone; 10, fludarabine; 11, Leukeran, vincristine, and prednisone; 12, bleomycin, lomustine, VP16, procarbazine, and prednisone (B-CEPP); 13, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), VP16, methotrexate, and prednisone; Ref, refractory to prior therapy; Rec, recurrent after therapy; Res, residual disease after therapy. *Skin involvement.
patients and their prior therapies and responses. Analysis of the responses to 2-CdA compared with prior chemotherapy responsiveness showed that 12 (41%) of the 29 refractory patients and four (40%) of the 10 patients with recurrent disease responded. The differences observed were not significant (Fisher's exact test one-sided P value = .62). The responding patients received two to five cycles of 2-CdA (median, two cycles). CRs occurred in five patients who received two cycles and three patients who received three cycles. PRs were observed in three patients who received two cycles, two patients who received three cycles, two patients who received four cycles, and two patients who received five cycles. Benefit was demonstrated after two or three cycles of 2-CdA, but patients were continued on therapy in an attempt to achieve a CR. The two patients who received five cycles were discontinued from therapy because of lack of further response, not because of drug toxicity. Toxicity
As with other phase II clinical trials of 2-CdA, little nonhematologic toxicity was experienced at a dose of 0.1
mg/kg/d. No patients experienced nausea, vomiting, mucositis, neurologic symptoms, or alopecia. No drug-related renal or hepatic toxicity was encountered. One patient had elevated creatinine levels during therapy. This patient had a pretreatment creatinine level of 1.4 mg/dL, which rose transiently to 2.4 mg/dL during the course of uric acid nephropathy and returned to pretreatment levels. Bone Marrow Suppression
Grade 3 or 4 neutropenia was experienced by seven of the 40 patients (18%). The nadir of neutrophil counts occurred between 7 and 14 days posttherapy. Recovery to baseline values usually occurred by 28 days posttherapy. Of the patients who experienced neutropenia, three of seven patients had documented sepsis. Two patients had Pseudomonas aeruginosa pneumonitis with sepsis, and the third had a Staphylococcus aureus intravenous
site infection. Grade 3 or 4 thrombocytopenia was seen in 12 of 40 patients (30%). Only one patient's platelet count fell below 20,000/pL. No life-threatening bleeding problems occurred. The nadir of the platelet count occurred
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375
2-CDA TREATMENT OF LYMPHOMAS
between 7 and 21 days posttherapy. Recovery of platelet counts occurred between 28 days and 42 days posttherapy. Only seven of the 107 cycles of 2-CdA were delayed because of cytopenia. We found evidence of cumulative myelosuppression with 2-CdA therapy. WBC counts fell on average to 95% (+ 11% SE) of the pretreatment value after two cycles of 2-CdA, 74% (± 6% SE) after three cycles, and 54% (± 4% SE) with four cycles of therapy. (Patients with a lymphomatous leukemic phase were excluded from analysis of WBC counts but not excluded from absolute neutrophil count analysis.) Absolute neutrophil counts were on average maintained after two or three cycles of treatment. On average, the mean granulocyte count actually improved with subsequent cycles of 2-CdA therapy. After two cycles, the mean granulocyte count rose to 130% of normal (± 24% SE) and, after three cycles, was 114% of normal (± 29% SE). The platelet counts fell to 80% (± 19% SE) of their pretreatment levels, with either two or three cycles of 2-CdA. No further decrement in the platelet count was observed beyond that observed after three cycles. Long-term follow-up of two patients who remain in CR after 33 and 29 months shows these patients to have normal complete blood cell counts with normal absolute neutrophil counts and normal absolute lymphocyte counts. Infectious Complications Five of 40 patients had documented bacteremias. Three of the five patients experienced gram-negative sepsis within 1 month of receiving 2-CdA therapy. In two of these three patients, P aeruginosa was identified. The third patient had Escherichiacoli isolated and was found to have appendicitis with perforation. Two of 40 patients experienced intravenous site infections. One patient had Serratiamarcescens infection of his central venous catheter, and in the second patient, a peripheral intravenous site infection was complicated by S aureus bacteremia. One patient experienced acute cytomegalovirus (CMV) pneumonitis, hepatitis, and, presumptively, encephalitis concomitant with a fulminant relapse and evolution of his disease 6 months after treatment. The diagnosis of acute CMV infection was made by examination of IgG titers. The patient's CMV IgG titer had risen to 1:23,768. The patient's liver enzymes were elevated with a hepatocellular pattern, alkaline phosphatase level of 60 U/L (normal, 35 to 108 U/L), total bilirubin level of 2.8 mg/dL (normal, 0.0 to 1.5 mg/dL), SGOT level of 321 U/L (normal, 9 to 50 U/L), and SGPT level of 456 U/L (normal, 8 to 62 U/L). Hepatitis A and B serologies
were negative. The patient had a diffuse interstitial pneumonitis on chest x-ray and was febrile to 39 0 C on multiple occasions. He was obtunded; no focal neurologic signs were present. Blood and urine cultures were negative for bacterial and fungal growth. CSF examination was normal except for an elevation of the protein at 90 mg/dL (normal, 15 to 45 mg/dL). This clinical pattern occurred 6 months after treatment with 2-CdA and in association with relapse. Thus, there is no evidence to suggest a CNS effect of the drug. Oral herpes simplex infection occurred in two patients, and dermatomal herpes zoster infection was seen in one patient during 2-CdA treatment. No patients developed disseminated herpes simplex or zoster infections. One patient who was receiving high doses of corticosteroids in addition to 2-CdA for autoimmune hemolytic anemia experienced recurrent pneumonias. Open-lung biopsy yielded the diagnosis of a granulomatous process that revealed no growth of mycobacterial or fungal cultures. However, the patient has responded to empiric antituberculous therapy. DISCUSSION The low-grade lymphocytic lymphomas are often indolent diseases, and patients may survive many years without treatment. Except in follicular mixed lymphomas, the survival of patients with low-grade lymphomas has not been convincingly changed by treatment. Although alkylating agents, prednisone, and combination chemotherapy can have a salutary effect on the symptoms and manifestations of the disease, the responses are often incomplete, and eventual relapses are the rule. This may be due in part to the fact that the low-grade lymphomas have a low growth fraction such that the majority of the malignant cells in these patients are nondividing lymphocytes. Despite excellent clinical responses to therapy, malignant lymphocytes may become resistant to the drugs or may be protected from their effects because the cells are not cycling. These residual cells result in relapse and are the reason new drugs are needed to treat these diseases more effectively. 2-CdA has been shown to achieve cytoreduction in advanced indolent B-cell neoplasms. This may be due in part to its ability to kill lymphocytes independently of cell division.' Consistent with our observations with chronic lymphocytic leukemia and hairy cell leukemia, this study has demonstrated a significant response rate with this single agent in the treatment of recurrent or refractory low-grade lymphomas. Especially important is the fact that eight of the 17 patients who responded
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KAY ET AL
376 experienced CRs, an uncommon observation with a single agent in extensively pretreated patients. Part of the difficulty inherent in treating patients with low-grade lymphomas is that they often evolve to highergrade histologies, conferring a worse prognosis. Such an evolution was documented in this study in six patients before therapy and two patients after therapy. Interestingly, analysis of our data according to presence or absence of histologic evolution showed no significant response differences in the groups: two of six patients responded in the group with evolution, and 14 of 34 responded in the group without evolution. The spectrum of toxicity of 2-CdA in this trial has been similar to that seen in studies of other low-grade B-cell malignancies with an absence of traditional chemotherapy side effects. The dose-limiting toxicity is myelosuppression, which occurs at an acceptable incidence in the doses used in this and other phase II trials of this agent in lymphoid malignancies. The infections seen were those that typically occur in lymphoma patients and with conventional chemotherapy. Cytopenias occurred in one third of the patients. Hematologic toxicity was observed principally in those patients who had been heavily pretreated and had extensive bone marrow involvement by their disease. Myleosuppression was cumulative, but long-term follow-up of two disease-free patients showed no abnormalities. However, there has been some experience with cumulative myelosuppression observed in patients with normal bone marrows. Four patients with multiple sclerosis were treated with the same dosage and schedule of 2-CdA as the lymphoma patients. These patients have manifested minimal suppression of their granulocyte, platelet, and absolute lymphocyte counts for up to 6 months posttreatment. While aggressive treatment strategies are emerging in
the treatment of certain low-grade lymphomas, including bone marrow transplantation, these techniques are still limited by the difficulties in achieving total or near-total cytoreduction with the available agents. It is clear that new agents are needed to accomplish this goal. This study of 2-CdA indicates that it may be such an effective agent. Fludarabine phosphate, another nucleoside with similar response rates in lymphocytic lymphoma,'. 15 6 will also be effective in the management of low-grade lymphomas. However, fludarabine is limited in its application for dose-intensive therapy because of dose-limiting CNS toxicity. 2-CdA is an agent that may be able to be dose-escalated in this setting. This agent has been given to 14 patients at twice the dosage used here with no organ toxicity except myelosuppression. Two of these 14 patients received two cycles of 0.2 mg/kg/d for 7 days. However, when given at considerably higher doses (0.4 mg/kg/d for 7 days followed by 0.5 mg/kg/d for 7 days sequentially) in conjunction with total body irradiation and cyclophosphamide (60 mg/kg for two doses), nephrotoxicity and neurotoxicity were observed.1 7 Whether or not the toxicity seen at the high doses was due to the drug alone or its combination with cyclophosphamide and total body irradiation is not known. These observations, however, suggest that 2-CdA may have a role in dose-intensive approaches. Further work in defining the ideal dose ranges for this application will be required. ACKNOWLEDGMENT We thank Dr Robert Lukes for his expertise in reviewing the biopsy materials. We acknowledge Drs Charles Kossman, Howard Davidson, Richard Anderson, the staff of the General Clinical Research Center, and Patricia A. Morin, RN, for their assistance in this project.
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2-CDA TREATMENT OF LYMPHOMAS kinase-mediated toxicity of deoxyadenosine analogs toward malignant human lymphoblasts in vitro and toward murine L1210 leukemia in vivo. Proc Natl Acad Sci USA 77:6865-6869, 1980 13. Cheson BD, Bennett JM, Rai KR, et al: Guidelines for clinical protocols for chronic lymphocytic leukemia: Recommendations of the National Cancer Institute-sponsored Working Group. Am J Hematol 29:152-163, 1988 14. Oken MM, Creech RH, Tormey DC, et al: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982
15. Redman J, Cabanillas F, McLaughlin P, et al: Fludarabine phosphate-A new agent with major activity in low-grade lymphoma. Proc Am Assoc Cancer Res 29:211, 1988 (abstr) 16. Kantarjian HM, Alexanian R, Koller CA, et al: Fludarabine therapy in macroglobulinemic lymphoma. Blood 75:1928-1931, 1990 17. Beutler E, Piro LD, Saven A, et al: 2-chlorodeoxyadenosine (2-CdA). A potent chemotherapeutic and immunosuppressive nucleotide. Leukemia and Lymphoma 5:1-8, 1991
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