Intensive combination chemotherapy (ROAP 10) and splenectomy in the management of chronic myelogenous leukemia.

Abstract

To investigate the role of intensive chemotherapy in chronic myelogenous leukemia (CML), we treated 37 patients who had Philadelphia-positive benign-phase disease with rubidazone 300 mg/m2/d 1 (or daunorubicin 30 mg/m2/d X 4), cytosine arabinoside 80 mg/m2/d X 10, vincristine 2 mg/d 1, and prednisone 100 mg/d X 5 (ROAP 10), every four weeks for a median of three cycles. This treatment was followed by splenectomy and by subsequent maintenance therapy with 1 to 5 g hydroxyurea daily in intermittent courses. After a median follow-up of 42 months (range, 24 to 54 months), 20 patients (54%) remain in benign phase. The projected median survival is 52 months, and the three-year survival rate is 67%. Six patients (16%) developed blastic crisis, and eight died in the benign phase. A significant cytogenetic response, defined as a fall in the percentage of Philadelphia-positive cells to less than or equal to 30%, occurred in 18 (53%) of 34 patients who had serial cytogenetic studies. Six patients (18%) had reductions to 35% to 90%, whereas ten remained 100% positive. Cytogenetic response lasted for a median of six months from the time of maximal response (range, 1 to 18 months). Blastic crisis or accelerated disease developed in seven (44%) of the 16 patients who manifested minimal or no cytogenetic response, compared to only two of the 18 patients (11%) who achieved a significant cytogenetic response. Toxicity, which resulted in one death, was due to myelosuppression and consisted of febrile episodes during neutropenia (24% of courses), documented infections (8% of courses), and bleeding (8% of courses). ROAP 10 intensive therapy produces moderate survival improvement for CML patients compared to a matched historical control group of patients treated at our institution, but it has considerable myelosuppressive toxicity. The Philadelphia chromosome response is an important treatment-related prognostic factor.

Unresponsiveness of primitive chronic myeloid leukemia cells to macrophage inflammatory protein 1 alpha, an inhibitor of primitive normal hematopoietic cells.

“…In vitro, high concentrations of TGF-f alone can clearly block the proliferation of primitive CML cells (Table 3 Regardless of the molecular mechanism underlying the observed differential responsiveness of primitive normal and CML cells to MIP-la addition to LTCs, the present findings may have implications for therapy where interactions of cytokines also occur in the context of a complex cellular environment. Several studies indicate that administration of MIP-la can be used to protect primitive murine hematopoietic cells (spleen CFU) from inactivation by cell cyclespecific drugs in vivo (21,22), including some that, in various combination chemotherapy protocols, have been effective in reducing (but not eliminating) the neoplastic clone in patients with CML (32,33). These latter clinical studies, together with in vitro data (11,12,34), have also established that substantial numbers of normal hematopoietic stem cells persist in many CML patients.…”

Specific Targeted Therapy of Chronic Myelogenous Leukemia with Imatinib

“…The 1970s saw a number of trials using acute leukemia-type multiagent chemotherapy. In contrast to conventional chemotherapy, a proportion of patients achieved some degree of Ph-negative hematopoiesis (Kantarjian et al, 1985). However, as a rule, these were transient responses.…”

Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro

“…7,8 However, alternative mechanisms, including possible antiapoptotic properties of BCR-ABL, have been proposed to explain the relative chemo-resistance of CML. 28,29 More recently, the application of novel flow cytometric techniques has enabled us to demonstrate that quiescent leukemic stem cells do indeed exist in the blood and bone marrow of all patients with chronic-phase CML.…”

“…This raises the possibility that the quiescent leukemic cells we have identified in patients with CML are likely to survive standard chemotherapy regimens, and it may explain the clinical observation that, unlike acute myeloid leukemia, CML cannot be eradicated by chemotherapy alone. 7,8 The recent development of a novel, molecularly targeted, anticancer agent has heralded a major breakthrough in leukemia therapy. [9][10][11] STI571 (Glivec; Novartis Pharmaceuticals, Basel, Switzerland) is a signal transduction inhibitor that acts specifically on the p210 BCR-ABL tyrosine kinase.…”