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A pilot study of alpha-interferon and plicamycin for accelerated phase of chronic myeloid leukemia

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A pilot study of alpha-interferon and plicamycin for accelerated phase of chronic myeloid leukemia
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  Pergamon PII: SO1452126(96)00108-7 Leukemia Research Vol. 21, No. 5, pp. 375-380, 1997. 8 1997 Elsevier Science Ltd. All rights reserved Printed in &eat Britain 0145.2126197 17.00 + 0.00 A PILOT STUDY OF ALPHA-INTERFERON AND PLICAMYCIN FOR ACCELERATED PHASE OF CHRONIC MYELOID LEUKEMIA* Janice P. Dutcher, Deborah Coletti, Elisabeth Paietta and Peter H. Wiernik Department of Oncology, Montefiore Medical Center/Albert Einstein Cancer Center, 111 East 210th Street, Bronx, New York, NY 10467, U.S.A. (Received 12 June 1996. Accepted 2 October 1996) Abstract--Thirteen patients with accelerated phase of chronic myeloid leukemia (CML-AC) were treated with intravenous plicamycin and subcutaneous alpha-interferon. Two patients stabilized, three patients had partial hematologic responses and one patient had a hematologic complete response with a major cytogenetic response. Two patients, progressing on hydroxyurea, did not respond, but demonstrated re-sensitization to hydroxyurea after completion of induction therapy and had prolonged return to chronic phase for 30 months and 25 months. Four non-responders subsequently received additional chemotherapy and responded. Median survival of all study patients from the development of accelerated phase of CML was 24 months: substantially longer than other reported series (median 6 months). Plicamycin appears to add efficacy to interferon in the stabilization of accelerated phase of CML. 0 1997 Elsevier Science Ltd. Key words: Chronic myeloid leukemia (CML), interferon, leukemia, plicamycin, accelerated phase CML, therapy-CML. Introduction Chronic myelogenous leukemia (CML), a clonal myelo- proliferative disorder of the hematopoietic stem cell, associated with the presence of the Philadelphia (Ph’) chromosome, is characterized by a progressive triphasic course in which the initial chronic phase of the disease is an indolent one (years), but is followed by an accelerated phase with usually rapid progression *Supported in part by Cancer Centre Core Grant P30CAl3330, awarded by the National Cancer Institute. The contents are solely the responsibility of the authors and do not necessarily represent the official view of the NCI. Presented in Part at the Annual Meeting of the American Society of Hematology 1992 Abbreviations: CML-BC, chronic myeloid leukemia, blast crisis; CML-AC, chronic myeloid leukemia, accelerated phase; Ph’, Philadelphia chromosome; SQ, subcutaneous; tiw, three times per week; CR, complete remission; PR, partial remis- sion; SD, stable disease; NR, no response; PD, progressive disease; Inv, inversion; Iso, isochromosome; cy, cytogenetic; TdT, terminal deoxynucleotidyl transferase; H, hydroxyurea; B, busulfan; I or Ij%, interferon; P, plicamycin; BMT, bone marrow transplant. Correspondence to: Janice P. Dutcher, MD, Department of Oncology, Montefiore Medical Center, 111 East 210th Street, Bronx, New York, NY 10467, U.S.A. (Tel: +1 718 920 4674; Fax +l 718 798 7474). (months) to a blastic (acute) phase that is resistant to chemotherapy (weeks) [l]. Single-agent chemotherapy (i.e. hydroxyurea or busulfan) has been characteristically utilized to control the chronic phase of CML by stabilizing the blood counts and splenomegaly, with resistance demonstrated during the accelerated phase. These agents have little impact on progression of the disease to blast phase, or on overall survival [2], although the chronic phase appears to be longer when treated with hydroxyurea than with busulfan [3]. Interferon has a direct antiproliferative effect on stem cells from CML patients, as well as an immunoregula- tory effect [4,5]. Overall survival is prolonged for patients who achieve a major cytogenetic response to this agent [6,7]. However, interferon alone has been much less successful in CML-AC [6,8]. Plicamycin is an inhibitor of DNA-dependent RNA synthesis [9]. In vitro, plicamycin induced differentiation of blast cells from a patient with CML in blast crisis, who subsequently appeared to respond clinically to a combination of plicamycin and hydroxyurea, as did others [lo, 111. Molecular studies done on the leukemic cells of the initial patient also demonstrated an apparent decrease in the mRNA coding for the proto-oncogenes C-myc and c-abl in the leukemic blast cells [lo]. This study was designed to test whether the addition of 375  376 J. P. Dutcher et al. Table 1. Criteria against number of patients and patient number for accelerated phase Criteria No. Patients and Patient number Lactate dehydrogenase > normal Rising WBC, despite previous control on therapy Progressive organomegaly despite initial control on therapy Platelets >106/p1 despite therapy Additional cytogenetic abnormalities Immature immunophenotype Marrow blasts >5% Symptoms (fever, night sweats, anorexia, bone pain, abdominal pain - rapid organomegaly) n = 13; all ranged 1.5-6 x normal n = 11; patients 1, 2, 5-13 n = 10; patients 1-7, 9, 12, 13 n = 3; patients 5, 6, 11 n = 3; patients 1, 3, 13 n = 7; patients 2, 4, 5, 7-9, 12 n = 6; patients 1, 6, 9-12 it = 6; patients 1, 3, 5-7, 12 plicamycin to interferon in accelerated phase of CML can enhanced the limited efficacy of interferon in this stage of the disease. There are data suggesting that plicamycin can induce differentiation of blastic CML cells and anecdotal clinical responses. Patients and Methods Diagnostic criteria All patients had a diagnosis of accelerated phase of CML, as defined by NC1 sponsored cooperative group leukemia committees [12]: A known diagnosis of chronic phase CML with the presence of the Philadel- phia chromosome, and/or one or more of the following: additional cytogenetic abnormalities, increasing spleno- megaly on hydroxyurea or busulfan, progression of hematologic parameters on standard treatment, but with less than 30% blasts plus promyelocytes or less than 20% lymphoid blasts in the marrow. Table 1 shows the distribution of these characteristics among the patients treated with this study regimen. Patients Between January 1987 and December 1991, 13 patients (seven female/six males) with the accelerated phase of CML were entered into this treatment protocol (Table 2). The median age was 51 years (range 35-74 years) and the median duration of chronic phase was 32 months (range l-109 months). Patient characteristics at entry to this study, characterizing the diagnosis of accelerated phase are listed in Tables 1 and 2. All patients demonstrated progressive disease, all with elevations of lactate dehydrogenase upon study entry and either organomegaly or elevations of blood counts or both. Features of accelerated CML include: A rising WBC count despite previously adequate therapy (11 patients); a platelet count greater than lo”/@ (3 patients); progressive organomegaly unresponsive to continued initial therapy for chronic phase (10 patients). Twelve of 13 patients had aspirable marrows which were hypercellular but with less than 30% blasts. Bone marrow biopsies confirmed this in all 13 patients. Twelve patients evaluable by marrow examination and one by peripheral blood at study entry had the Ph’ chromosome and three had additional cytogenetic abnormalities: Isochrome 17 (patient 3), inversion 3 (patient 13) and complex cytogenetic abnormalities (patient 1). All but one patient expressed only myeloid antigens: six patients were immunophenotypically mature, six had accelerated phase, one of whom expressed TdT in 40% of cells suggesting transition to lymphoid blast crisis and one was immunologically blastic (myeloid). These features did not correlate with cytogenetic changes, as previously reported by us [13]. In fact, the three patients with additional cytogenetic abnormalities, a defining characteristic of acceleration, were immunologically still mature. Previous therapy Treatment during the chronic phase included hydro- xyurea (10 patients), busulfan (seven patients) and leukopheresis (two patients) and those receiving med- ication were progressing on their previously effective therapy. Only one patient had previously received alpha- interferon during chronic phase without benefit. One patient presented in accelerated phase with a blastic immunophenotype and was entered on the study protocol without prior therapy. Treatment regimen Treatment included a 2 week induction therapy: plicamycin, 25 @kg as an intravenous infusion over 2-4 h, three times a week (tiw) for 2 weeks; and interferon, 5 x lo6 U/m2, as a subcutaneous (SQ) injection tiw, alternating days with plicamycin. Maintenance therapy followed 2 weeks of induction therapy, consisting of interferon, 5 x lo6 U/m2 SQ tiw and plicamycin, 25 pg/kg, once per month. Plicamycin and interferon were continued until disease progression or until drug intolerance to one or both agents. Patients who developed dose-limiting toxicity to plicamycin were allowed to continue with interferon. Dosage  378 J. P. D&her et al. adjustments were made for hepatic and hematologic toxicity and for decreased performance status. Criteria for response Objective response, according to criteria utilized for cooperative group clinical trials [12], required a hematologic response with or without a cytogenetic response. A complete hematologic and clinical remis- sion was defined as normalization of peripheral blood counts, including a normal differential count without immature forms (blasts, promyelocytes and myelocytes), disappearance of all clinical symptoms related to CML (including fever, malaise, painful splenomegaly), reduc- tion in spleen size to non-palpable, and marrow with less than 5% blasts. Partial hematologic remission was defined as 250% reduction in white blood count from pretreatment, with possible persistence of a palpable spleen or immature cells in the peripheral smear. Stable disease was defined as <50% reduction in white blood cell count from pretreatment, without progression of other symptoms. Cytogenetic remission was determined by assessing at least 10 metaphases for reduction in cells containing the Ph’ chromosome or other known cytogenetic abnorm- alities. A complete cytogenetic response was defined as the absence of all abnormalities. A partial cytogenetic response required 5-34% of metaphases with the Ph’ chromosome. Immunophenotype was monitored throughout treatment, but was not included in response definition. Clinical Results Seven of 13 patients (patients 1-7) had no objective response to study treatment, but patients 4-7 had prolonged survival compared with historical data on patients in accelerated/blastic phase of CML [13-161 (Table 3). After 1 month of study therapy, patient 4 underwent allogeneic bone marrow transplant in accel- erated phaseiblastic phase and remained stable for 8 months (12 month survival from accelerated phase). Patient 5 showed eradication of her TdT+ cells with the study regimen but progressed to blast crisis. She returned to chronic phase with mitoxantrone and carboplatin, but died in chronic phase of complications secondary to allogeneic bone marrow transplantation with a survival from accelerated phase of 21 months. Patients 6 and 7 were progressing on hydroxyurea and demonstrated a re-sensitization to hydroxyurea after completion of study treatment. Both patients had increasing splenomegaly and white blood cell count, and patient 6 had increasing immature myeloid forms in the marrow, hepatomegaly and thrombocytosis with fever, night sweats and anorexia. Both received induc- tion plicamycin and interferon with minimal response. However, after reinitiating hydroxyurea at the previous dose, patient 6 returned to chronic phase lasting 30 months with only hydroxyurea maintenance and patient 7 returned to chronic phase lasting 25 months with hydroxyurea plus interferon. Patients 8 and 9 stabilized in accelerated phase with this regimen for 20 and 14 months, respectively, before developing blast crisis. Patient 9 responded to mitoxan- trone and cytarabine for blast crisis and underwent autologous bone marrow transplantation 6 months later but did poorly. Nevertheless, she survived 21 months from diagnosis of accelerated phase. Three patients (10, 11, 12) had partial hematologic responses to this regimen. Patient 10 is alive and maintained his restored chronic phase after induction for 79 months, receiving intermittent interferon and plica- mycin as maintenance therapy. He has recently devel- oped blast crisis and is pursuing other therapy. Patient 11 received only one dose of plicamycin, and was removed from study due to hepatic toxicity. However, she continued with interferon and intermittent hydro- xyurea and had a reversal of accelerated disease (resolution of progressive hepatosplenomegaly, throm- bocytosis and megakaryocytosis) with return to a stable chronic phase lasting 58 months. Her death in chronic phase was due to pulmonary complications possibly related to prior alkylating agent therapy. Patient 12 achieved a partial hematologic response after 2.5 induction courses. He has been maintained on interferon with intermittent hydroxyurea and has been stable for 72+ months. Finally, patient 13 has had a complete hematologic response after 3 months of therapy and has had progressive improvement in cytogenetics while on maintenance therapy, qualifying as a partial cytogenetic response to this regimen. Initially, she had 20120 metaphases bearing the Ph’ chromosome and 6/20 metaphases bearing Inv 3. After 2 months of treatment, cytogenetic studies showed 100% of metaphases with the Ph’ chromosome only and no Inv 3. After 26 months of treatment, 17 of 20 metaphases were normal with only 3120 containing the Ph’ chromosome. She con- tinues on therapy with interferon and intermittent plicamycin at 57+ months, continuing in hematologic complete remission and cytogenetic partial remission. Discussion This paper presents data on a typical group of patients with clinical features of accelerated phase of CML (Tables 1 and 2), with the median time from diagnosis to accelerated phase of 32 months (range l-109 months) (Table 2). At the time of entry, all of these patients had poor prognostic features outlined by Sokal et al. to predict for shorter survival in chronic phase, including  379 licamycin and interferon in accelerated CML INTERFERON + PLICAMYCIN IN ACCELERATED PHASE CML i 20-- V --- i lo-- \ L--_-- ii 0 I I I I I I I I I I 1 I L I I I I I I I I I I 1 I 1 0 12 24 36 46 60 72 64 96 108 120 132 144 156 months Fig. 1. Survival of patients treated with plicamycin plus interferon divided into total survival (thin solid line), time in chronic phase (dotted line) and survival in accelerated phase (heavy solid line). splenomegaly and/or hepatomegaly, elevated white blood cell count and lactate dehydrogenase, increased marrow blasts in six patients, and additional cytogenetic abnormalities in three patients [17, 181. All were progressing through standard therapy, and demonstrated a marked change in their previous clinical behavior. These patients were treated prior to the routine initiation of interferon therapy for chronic phase of CML, so that only one patient had previously received that agent. However, current data suggest that interferon is of marginal benefit in the accelerated phase of CML [6,8]. As for the aggressive treatment of accelerated phase, the median survival during treatment with chemotherapy in three reported studies in which accelerated and blastic phase patients were included was approximately 6 months [13-E]. A more recent paper of intensified chemotherapy reported that among 24 patients treated in accelerated phase, six achieved complete response lasting a median of 10 months [16]. The median survival of all accelerated phase patients was 8 months with 30% alive at 18 months [16]. Bone marrow transplantation in accelerated phase has for the most part been accompanied by high mortality and poor outcome, with 10% alive at 5 years. However, a more recent report suggests that a select subgroup of such patients, with cytogenetic progression only, and no clinical features of acceleration may have a considerably improved outcome [19]. These are not the patients in this study. In our study, four patients had objective responses (one CR, three PR) and two patients stabilized, allowing subsequent therapy and return to chronic phase. Three patients (one SD, two NR) stabilized sufficiently with this regimen to undergo either allogeneic or autologous BMT, with some prolongation of survival (12, 20, 23 months). Two additional patients had an uncharacter- istic ‘resensitization’ to oral hydroxyurea, one in conjunction with continued interferon, with return to chronic phase and prolonged survival. This may represent a finding similar to that recently reported by Jehn et al., of the successful treatment of accelerated and blastic CML with high dose interferon and hydroxyurea [20]. Finally, the hematologic complete responder has also had a major cytogenetic response and continues to respond. The median survival of these patients after develop- ment of accelerated phase of CML is 24 months, with 4/ 13 surviving 25 years, which is substantially longer than expected from previous clinical reports of patients in this advanced stage of CML [13-16, 191. The duration of survival did not correlate with the dose of plicamycin given, and it seems that very limited exposure to plicamycin in addition to interferon was able to produce stabilization of the disease course even in patients with no objective response. Two of the patients with long- term response (patients 10 and 13) continued to receive intermittent plicamycin in addition to interferon, and two others (patients 11 and 12) have been maintained with interferon and hydroxyurea. Figure 1 demonstrates the overall survival from diagnosis (thin solid line), time from CML diagnosis to accelerated phase (dotted line), and the survival in accelerated phase (heavy solid line). These curves suggest that the overall survival of these patients is improved due to prolonged survival in accelerated phase. In summary, this group of patients, although small, is representative of patients with advanced accelerated phase of CML [13-16,191. The outcome in terms of
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