High-Dose Methotrexate With Folinic Acid in the Treatment of Advanced Non-Hodgkin Lymphoma Including CNS Involvement

Transcription

1 High-Dose Methotrexate With Folinic Acid in the Treatment of Advanced Non-Hodgkin Lymphoma Including CNS Involvement By Arthur T. Skarin, Kenneth S. Zuckerman, Susan W. Pitman, David S. Rosenthal, William Moloney, Emil Frei Ill, and George P. Canellos High-dose methotrexate with folinic acid (MTX/FA) was evaluated in 20 patients (16 previously treated) with advanced non-hodgkin lymphoma (NHL). All had unfavorable diffuse histology (poorly differentiated lymphocytic, 13; histiocytic, 6; undifferentiated, 1). The dose schedule range was g/sq m administered every 1-3 wk with hydration and urinary alkalinization. Of the 20 patients, 12 (60%) had an objective response, including 4 (20%) complete responses (CR), with a median CR duration of 4.5 mo and a median partial response duration of 1.5 mo. Six patients had central nervous system (CNS) involvement and 5 of these responded; 3 had complete disappearance of CNS disease, with 1 of these remaining in remission 14 mo after MTX/FA. A median of 7 courses per patient (range 3-20) was administered, with untoward reactions independent of the dose of MTX. At least one type of toxicity occurred in 19 of 156 (12%) courses, but no drugrelated deaths occurred. As with other agents, use of high-dose MTX/FA as a single agent in refractory disease has been limited because responses, although dramatic, are generally brief. MTX/FA in combination with other agents in newly diagnosed cases of unfavorable histology NHL may result in improved response rates, decreased occurrence of CNS lymphoma, and prolongation of disease-free survival. C OM BINATION CH EMOTH ERAPY PROG RAMS effective in the treatment of non-hodgkin lymphoma (NHL) are comprised of agents whose activity has been ascertained in patients refractory to previous therapy. 2 To date, alkylating agents, corticosteroids, ymca alkaloids, Adriamycin, and Bleomycin in various combinations represent the principal armamentaria for the treatment of NHL with unfavorable histology (mainly diffuse lymphocytic or histiocytic lymphomas). Despite a high initial response rate, a significant number of patients sustain a recurrence of their disease. Relapse of the disease following initial success is characterized in many instances by (I) relapse of systemic disease between cycles of myelotoxic therapy, even before the blood counts have recovered,3 4 and (2) central nervous system (CNS) lymphomatosis, usually manifested as meningeal involvement.3 5 From the Divisions of Medical Oncology and Hematology. Sidney Farber Cancer Institute, Peter Bent Brigham Hospital. and Harvard Medical School, Boston. Mass. Submitted March 8, /977; accepted July /8, Supported in part by USPHS Research Grant C-6516 from the National Institutes of Health. Grant RR00888 from the Division of Resources. General Clinical Research Centers Branch. and the Nehemius Gorin Foundation, Boston. Mass. Presented at the / 9th Annual Meeting, A merican Society of Hematology, Boston. Mass.. December 7, /976. Address for reprint requests: A rthur T. Skarin. M.D.. Sidney Farber Cancer Institute, 44 Binney Street, Boston, Mass /977 by Grune & Stratton, Inc. ISSN Blood, Vol. 50, No. 6 (December),

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3 MTX/FA IN NON-HODGKIN LYMPHOMA 1041 The antimetabolites have had only limited success in the treatment of malignant lymphomas. Drugs such as cytosine arabinoside and methotrexate (MTX) have shown some order of activity,6 but their inclusion in combination chemotherapy programs has been restricted because of associated myelosuppression.7 It has been shown that the toxic effects of MTX can be reversed by the timely administration of citrovorum factor, otherwise known as folinic acid (FA).81#{176} Recent investigations have demonstrated that even high doses (3-7.5 g/sq m) of MTX can be administered safely, and in the majority of cases the myelotoxicity and mucous membrane lesions characteristic of MTX toxicity have been prevented.2 Furthermore, pharmacologic investigations of cerebrospinal fluid (CSF) concentrations of MTX have demonstrated that the higher dose MTX regimens can result in cytotoxic concentrations in spinal fluid after systemic administration of the drug.3 Thus, in planning new programs for the treatment of patients with NHL of unfavorable histology, high doses of MTX with FA rescue (MTX/FA) would be very appealing, not only for the ability to administer the agent without enhancing myelotoxicity, but also as a possible prophylactic treatment for the prevention ofcns relapse. To that end, an investigation of high-dose MTX/FA was undertaken in a population of patients with unfavorable histology NHL, the majority of whom were refractory to previous cytotoxic therapy. In addition, a number of these patients had CNS disease as part of the advancing state of their lymphoma. The effectiveness of MTX/FA in the latter patients is also considered. MATERIALS AND METHODS The clinical and pathologic characteristics of 20 patients with advanced disease are shown in Tables 1 and 2. Histopathology was categorized according to the Rappaport classification.14 All patients had unfavorable histology (diffuse poorly differentiated lymphocytic, 13, diffuse histiocytic, 6, diffuse undifferentiated, I) and were staged by procedures previously described3 as stage III (2) or IV (18). The median age was 49 yr (range yr) with a male:female ratio of 13:7. Sixteen patients had received prior combination chemotherapy, including irradiation in six patients. Four previously untreated patients received high-dose MTX/FA with response evaluation at 4 wk before for initiation ofcombination chemotherapy. Informed consent was obtained in all cases. Patients were required to have a creatinine clearance greater than 60 mi/mm and a normal intravenous pyelogram. Alkalinization of the urine was achieved by administration of sodium bicarbonate, 3 g by mouth every 3-6 hr the night before MTX infusion and for 48 hr thereafter.11 5 Hydration with at least 3 liters of fluid per day was maintained throughout each course. MTX was administered by intravenous infusion over mm in an initial dose of I g/sq m, with gradual escalation in most patients to g/sq m if toxicity did not develop at the lower previous dose. FA (10 mg/sq m) was given intravenously 24 hr after the MTX and was continued at 10 mg/sq m orally every 6 hr for 72 hr. If the serum creatinine increased by more than 50#{176},, above baseline level at 24 hr, then FA was increased to 100 mg orally every 3 hr until the serum MTX level decreased to less than I x l0 M. Courses of MTX/FA were given weekly at the outset but eventually intervals were increased to every 2-3 wk in responding patients. Complete response (CR) was defined as the complete regression of all measurable disease in excess of 1 mo. Partial response (PR) was defined as greater than 50#{176}/a,reduction in measurable lesions lasting more than I mo. Nonresponders (NR) included patients with progressive disease, *Slides were reviewed by Dr. Geraldine Pinkus, Department of Pathology, Peter Bent Brigham Hospital.

4 1042 SKARIN El AL. those with less than 50% reduction of disease, and those with complete or partial disease regression lasting less than I mo. Response duration was measured from the time of achieving maximal response to the time of relapse; survival was calculated from the first day of therapy. Response was determined after a minimum of three courses and was confirmed by repeat biopsy of marrow or other accessible tissue without resorting to a laparotomy or laparoscopy. Serum MTX levels were determined by radioimmunoassay at 24 hr in all Serial daily determinations were obtained in the presence ofelevated serum creatinine. RESULTS A median of 7 courses of MTX/FA per patient (range 3 20) was administered. Serum MTX levels at 24 hr as related to dose were comparable to levels obtained in other patients with a variety of neoplasms, with median values of I x l0_6 M to 5 x l0 M after 1 to 7.5 g/sq m, respectively. Of the 20 patients, 12 (60%) responded, including 4 (20) with complete regression of all clinically measurable disease (Tables I and 2). All 4 patients with CR were in the group that received prior therapy; 2 of 4 previously untreated patients had a PR. The latter 2 patients subsequently achieved a CR with combination chemotherapy. Disease regression occurred rapidly, with most responses evident within 1-3 wk. Median duration of CR was 4.5k mo, with a range of 2 mo- l4 mo. Half ofthe complete responders remained free of disease at 7 and l4 mo. Median duration of PR was 1.5 mo. Of 8 patients with PR, 5 expired of progressive disease 3-8 mo after start of MTF/FA. Although 8 patients were classified as NR, cases 1 1 and 12 had a complete regression of measurable disease that was brief, lasting less than 1 mo, and case 13 achieved a CR in the CNS only. The response to systemic MTX/FA in 6 patients with CNS involvement was of particular interest since this complication developed while the patients were receiving or soon after they had completed systemic chemotherapy (Table 3). Concurrent CNS irradiation was not carried out, although 1 patient had prior CNS irradiation for unilateral blindness (case 1). Four patients had received corticosteroids (cases 1, 8, 13, and 14). The patients were treated initially with MTX/FA, at doses of g/sq m weekly. CSF levels of MTX were determined at 24 hr in 3 patients with values ranging from 3.3 x l0 M to 1.0 x l06m, which were approximately 50#{176}/a of corresponding serum levels. 3 CSF protein was markedly elevated in all 55 patients in whom it was measured, and malignant cells were identified in the CSF of 4 of the 5 patients. Two Table 3. MTX/FA Thera py of CNS Lymphoma CSF CNS Response Patient CSF Protein to MTX/FA Survival No.#{176} Clinical Cytologyt (mg/dl) (mo) mo) 1 Headache, back pain CR Headache, cranial n. palsy CR Headache, confusion, leg paralysis PR Headache, seizure, Cl scan positive ND ND PR Headache, confusion, Cl scan positive CR Headache, cranial n. palsy, leg weakness NR 3 *5cc Table 1. t +, malignant cells present; -, malignant cells absent; ND, not done.

5 MIX/FA IN NON-HODGKIN LYMPHOMA 1043 Fig. 1. Brain scan of case 10 (A) before and (B) after weekly high-dose MTX/FA for 5 wk. Marked reduction in the size of the mass lesion is evident.

6 1044 SKARIN El AL. Table 4. MTX Toxicity (No. of Courses) Total Dose No. of WBC Platelets (g/sq m) Courses <2000/cu mm <100,000/cu mm Mucositis Renal Gl Hepotic CNS Total cases had focal mass lesions on radionuclide brain scan. Objective disease regression was achieved in 5 of 6 patients, with complete reversal of laboratory and clinical abnormalities in 3 patients. Ofinterest, case 10 (Table 3 and Fig. I) developed a partial response after 1 g/sq m/wk with greater than 50 decrease in the size of a mass lesion, but relapsed at 6 wk. With an increased dose of MTX to 3 g/sq m and later to 7.5 g/sq m/wk, a second regression was achieved that lasted for 2 mo. Case 3 remained in complete remission at l4 mo. Case 1 relapsed at 2 mo after the interval for MTX/FA was increased to every 3 wk. The remaining patients expired from progressive systemic lymphoma. Side effects were independent of the dose of MTX; they are summarized in Table 4. Of 156 courses, 5 (3%) resulted in mild renal insufficiency. Serum creatinine did not exceed 1.9 mg/dl and returned to baseline level, usually within 1 wk. In 3 of these 5 courses myelosuppression did not occur, presumably because of the increased and frequent administration of FA as described in Materials and Methods. Myelosuppression in 2 courses was not prevented, although the modified dose of FA employed in the early part of the study was only 30 mg/sq m. Myelosuppression without increase in serum creatinine above 50% of baseline occurred during 5 courses. Multiple factors were involved, including failure to increase the dose of FA, extensive prior myelosuppressive therapy, and lymphomatous marrow involvement. Thus, in 7 (4%) of 156 courses some degree of myelosuppression occurred that was transient, lasting only 7-10 days, and without serious infection or hemorrhage. Oral mucositis ofmoderate degree was seen in 5 courses (3#{176}/a). Gastrointestinal toxicity was observed during 9 courses (6%), with moderate to severe vomiting lasting more than 6 hr in only 2 instances. One patient (case I) with recurrent meningeal lymphomatosis developed acute progressive dementia following reinstitution of MTX/FA. In summary, at least one type of toxicity occurred in 19 (12%) of 156 courses, with 10 of these courses involving multiple toxicities. No drug-related deaths occurred. DISCUSSION In the present study, high-dose MTX/FA employed as a single agent resulted in impressive disease regression in adults with advanced diffuse histiocytic or poorly differentiated lymphocytic lymphoma. Sixty per cent of patients had objective responses, including CR in 4 (20%) of 20 patients. The majority of patients were refractory to cytotoxic agents, presenting a major therapeutic

7 MTX/FA IN NON-HODGKIN LYMPHOMA 1045 challenge. High-dose MTX/FA in children with advanced NHL has demonstrated impressive response rates (CR in 8 of 1 1 and PR in 3 of I I), with prolonged unmaintained remissions following intensive maintenance cyclic combination chemotherapy for 2-3k yr. 7 In adults with diffuse histiocytic lymphoma, Berd et al. have also reported prolonged remission in 5 of 17 patients after combination sequential chemotherapy employing cyclophosphamide, vincristine, cytosine arabinoside, and MTX/FA.7 MTX in the latter study was administered weekly (x8) at a dose of 120 mg/sq m. Similar results with a modified program have been recently reported. The rationale for employing high doses of MTX/FA in this study is based upon several factors: A higher therapeutic ratio may be achieved in some tumors when compared to conventional-dose MTX. Standard doses of MTX in osteogenic sarcoma have resulted in low response rates, but with the use of weekly high-dose MTX/FA as many as 88% of patients may show objective disease regression 9 with avoidance of major toxicity. Likewise, MTX in vanous standard-dose schedules has generally been unsatisfactory in lymphoma, with response rates of 29 and associated myelosuppressive toxicity.6 The pharmacologic mechanisms involved in this approach to cancer chemotherapy have been discussed in detail20 and involve differences between carrier-mediated cell membrane transport systems of tumor cells versus normal marrow cells. Thus, in certain tumors, FA may selectively rescue normal cells rather than tumor tissue. Recent work has shown that MTX, although it primarily inhibits thymidylate synthesis, may also inhibit punine biosynthesis.2#{176} Rapidly growing tumors with a high growth fraction, such as diffuse histiocytic lymphoma, may be particularly sensitive to MTX/FA, as evidenced by the rapid and dramatic response noted in our patients. This rapid regression, however, may be of short duration when MTX is used alone. Achievement of therapeutic levels of MTX in the CSF after systemic administration of high doses, as determined in our studies as well as those of others, 3 2 suggests a possible role in the pnophylaxis ofcns infiltration. Recent studies from our institution,3 as well as the National Cancer Institute,5 have revealed an apparent increased incidence of CNS involvement with unfavorable histology NHL occurring in 25#{176}/-30% of cases. While irradiation, corticosteroids, and intrathecal chemotherapy have usually resulted in temporary improvement, the results of the current study show that high-dose MTX/ FA may be equally effective. Since lymphomatous disease may occur as a mass lesion, or may involve the leptomeninges, or both, cranial irradiation may have limited utility in prophylaxis. Intnathecal agents have pharmacologic limitalions, as recently noted,22 with irregular distribution of intrathecally administered MTX through the subarachnoid space. In addition, the majority of patients have or will develop accompanying systemic disease, which can also respond to MTX/FA. A major potential toxicity of high-dose MTX/FA involves the deposition of MTX crystals within proximal renal tubules, with resultant high and prolonged serum MTX levels and subsequent myelosuppression and mucositis. In the earlier studies with this agent variable nephrotoxicity occurred in 59#{176} of patients, with 55#{176}/a of the latter developing myelosuppression. However, with hydration and urinary alkalinization, nephrotoxicity was reduced to 4#{176}/s of

8 1046 SKARIN El AL. courses)5 In the present study, only 5 (3%) of 159 courses resulted in transient nephrotoxicity. When creatinine increased above 50% of the baseline level, administration of FA at high doses for 3-5 days avoided subsequent myelosuppression in the majority of instances. The importance of hydration, urinary alkalinization, and dose monitoring ofcreatinine and MTX levels after this type of high-dose administration has recently been emphasized)5 23 Use of high-dose MTX/FA as a single agent in advanced disease refractory to conventional agents, as noted in this report, is limited because responses, although dramatic, are generally short lived. The data, however, suggest a possible important role for high-dose MTX/FA combined with other active agents in newly diagnosed patients with unfavorable histology NHL. With acceptable toxicity, as reported in this study, use of MTX/FA between courses of myelosuppressive agents, when relapse often occurs, may result in improved CR rates, decreased occurrence of CNS lymphoma, and prolonged disease-free survival.24 ACKNOWLEDGMENT The authors express appreciation to Dr. James Tullis, New England Deaconess Hospital, and Dr. Lowell Schnipper, Beth Israel Hospital, for referral of patients, and to the Clinical Center Nurses, Sidney Farber Cancer Institute, and Virginia Dunn, R. N., Hematology Division, Peter Bent Brigham Hospital, for patient care and protocol assistance. The clerical help of Adele Joseph is also deeply appreciated. REFERENCES I. Skarin AT, Frei E III, Moloney WC, Gutterman GU: New agents and combination chemotherapy of non-hodgkin s lymphoma. Br J Cancer 31: , Bonadonna G, Lattuada A, Banfi A: Recent trends in the treatment of non-hodgkin s lymphomas. Eur I Cancer 12: , Skarin AT, Rosenthal DS, Moloney WC, Frei E Ill: Combination chemotherapy of advanced non-hodgkin lymphoma with bleomycin, Adriamycin, cyclophosphamide, yincristine, and prednisone (BACOP). Blood 49: , Schein PS, DeVita VT Ir, Hubbard S. Chabner BA, Canellos GP, Berard C, Young RC: Bleomycin, Adriamycin, cyclophosphamide, vincristine, and prednisone (BACOP) combination chemotherapy in the treatment of advanced diffuse histiocytic lymphoma. Ann Intern Med 85: , Bunn PA Jr. Schein PS, Banks PM, Dc- Vita VT Jr: Central nervous system complications in patients with diffuse histiocytic and undifferentiated lymphoma: Leukemia revisited. Blood 47:3-10, Livingston RB, Carter SK: Single Agents in Cancer Chemotherapy. New York, IGI/ Plenum, I970, pp Berd D, Cornog I, DeConti RC, Levitt M, Bertino IR: Long-term remission in diffuse histiocytic lymphoma treated with combination sequential chemotherapy. Cancer 35: , Goldin A, Mantel N, Greenhouse SW, Venditti JM, Humphreys SR: Estimation of the antileukemic potency of the antimetabolite aminopterin, administered alone and in combination with citrovorum factor or folinic acid. Cancer Res 13: , Hryniuk WM, Bertino JP: Treatment of leukemia with large doses of methotrexate and folinic acid. Clinic-biochemical correlates. I Clin Invest 48: , Levitt M, Mosher MB, DeConti RC, Farber LR, Skeel RT, Marsh IC, Mitchell MS. Papac RI, Thomas ED, Bertino IR: Improved therapeutic index of methotrexate with leucovorin rescue. Cancer Res 33: , 1973 II. Pitman SW, Parker LM, Tattersall MHN. Jaffe N, Frei E Ill: Clinical trial of high-dose methotrexate with citrovorum factor (NSC- 3590)-Toxicologic and therapeutic observations. Cancer Chemother Rep [Pt 3] 6:43 49, Djerassi I: High-dose methotrexate (NSC-740) and citrovorum factor (NSC-3590)

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10 : High-dose methotrexate with folinic acid in the treatment of advanced non-hodgkin lymphoma including CNS involvement AT Skarin, KS Zuckerman, SW Pitman, DS Rosenthal, W Moloney, E 3d Frei and GP Canellos Updated information and services can be found at: Articles on similar topics can be found in the following Blood collections Information about reproducing this article in parts or in its entirety may be found online at: Information about ordering reprints may be found online at: Information about subscriptions and ASH membership may be found online at: Blood (print ISSN , online ISSN ), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC Copyright 2011 by The American Society of Hematology; all rights reserved.