A randomized study of interferon-alpha versus interferon-alpha and low-dose arabinosyl cytosine in chronic myeloid leukemia.

Interferon-alpha (IFN-alpha) has significantly prolonged survival in chronic myeloid leukemia (CML), but some patients do not respond and many responses are not durable. To improve the results, IFN-alpha has been combined with other treatments, but so far only the association with low-dose arabinosyl cytosine (LDAC) has been shown to increase the response rate and to prolong survival. Here are reported the results of a study of 538 Philadelphia chromosome-positive CML patients who were assigned at random to treatment with IFN-alpha 2a alone or in combination with LDAC. The scheduled dose of IFN-alpha 2a was 5(6) IU/m(2)/d. The scheduled dose of AC was 40 mg/d for the first 10 days of each month of treatment. The efficacy endpoints were a complete hematologic response rate at 6 months (62% in the IFN-alpha-plus-LDAC arm versus 55% in the IFN-alpha arm; P =.11), major cytogenetic response (MCgR) rate at 24 months (28% versus 18%; P =.003), and overall survival (5-year survival, 68% versus 65%; P =.77). Treatment did not affect overall survival within different prognostic risk groups: low, intermediate, or high. Also the duration of MCgR was identical. The results of this study confirm the results of a similar French study only for the response rate, not for survival, suggesting that the relationship between cytogenetic response and survival may be extremely variable and that a meta-analysis of these and other studies of IFN-alpha versus IFN-alpha plus LDAC is required to settle the issue of the role of LDAC in the treatment of CML.

Chemotherapy for mobilisation of Ph-negative progenitor cells from patients with CML: impact of different mobilisation regimens.

Mobilised peripheral blood stem cells are widely used for autografting in patients with chronic myeloid leukaemia (CML) and it is generally thought that a high proportion of Ph-negative progenitor cells in the graft is desirable. We report here the results of 91 stem cell mobilisations performed with various chemotherapy regimens followed by G-CSF. We show that mobilisation of Ph-negative cells is possible after diagnosis as well as in advanced stages of the disease. The yield of Ph-negative cells is highly dependent on the chemotherapy regimen: while the combination of idarubicin and cytarabin for 3-5 days (IC3-5) mobilised Ph-negative cells in most patients, high-dose cyclophosphamide was ineffective. Mobilisation of Ph-negative progenitor cells after IC3 was at least as effective as after IC5; however, less apheresis sessions were required, and toxicity was much reduced after IC3. Compared to historical controls, IC was equally effective as the widely used ICE/miniICE (idarubicin, cytarabin, etoposide) protocol. No correlation was found between graft quality and the cytogenetic response to subsequent treatment with interferon-alpha. We conclude that IC3 is an effective and well-tolerated regimen for mobilising Ph-negative cells that compares well with more aggressive approaches such as IC5 and ICE/miniICE.

Postremission therapy in older patients with de novo acute myeloid leukemia: a randomized trial comparing mitoxantrone and intermediate-dose cytarabine with standard-dose cytarabine.

The treatment of older patients with acute myeloid leukemia (AML) remains unsatisfactory, with complete remission (CR) achieved in only approximately 50% and long-term disease-free survival in 10% to 20%. Three hundred eighty-eight patients (60 years of age and older) with newly diagnosed de novo AML were randomly assigned to receive placebo (P) or granulocyte-macrophage colony-stimulating factor (GM-CSF) or GM in a double-blind manner, beginning 1 day after the completion of 3 days of daunorubicin and 7 days of cytarabine therapy. No differences were found in the rates of leukemic regrowth, CR, or infectious complications in either arm. Of 205 patients who achieved CR, 169 were medically well and were randomized to receive cytarabine alone or a combination of cytarabine and mitoxantrone. With a median follow-up of 7.7 years, the median disease-free survival times were 11 months and 10 months for those randomized to cytarabine or cytarabine/mitoxantrone, respectively. Rates of relapse, excluding deaths in CR, were 77% for cytarabine and 82% for cytarabine/mitoxantrone. Induction randomization had no effect on leukemic relapse rate or remission duration in either postremission arm. Because cytarabine/mitoxantrone was more toxic and no more effective than cytarabine, it was concluded that this higher-dose therapy had no benefit in the postremission management of older patients with de novo AML. These results suggest the need to develop novel therapeutic strategies for these patients. (Blood. 2001;98:548-553)

High remission rate in acute myeloblastic leukemia with only two days of chemotherapy.

Twenty five patients with AML who had neither a history of toxic exposure or myelodysplasia were treated with a remission induction regimen consisting of two pulses of chemotherapy separated by 96 hrs. Each pulse consisted of cytarabine 2gm/m(2) (at t=0 and t=12 hrs) with mitoxantrone [30mg/m(2) ] administered immediately after the second cytarabine administration. Amifostine was administered three times a week [on Monday, Wednesday, and Friday] until the outcome of therapy was known. This regimen induced complete remissions in 15 of 17 patients less than 70 years of age and in 5 of 8 patients older than 70 years.

Results of topotecan-based combination therapy in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia.

The efficacy and safety of topotecan and high-dose cytarabine were evaluated in 59 patients with advanced myelodysplastic syndromes (MDS) (n = 38) or chronic myelomonocytic leukemia (CMML) (n = 21). Topotecan 1.25 mg/m2/d was administered by continuous Intravenous infusion daily for 5 days, and cytarabine 1.0g/m2/d by Infusion over 2 hours for 5 days. At a median follow-up duration of 7 months, 59 patients were evaluable for response and toxicity. Complete remission (CR) was achieved in a significantly larger proportion of MDS patients than CMML patients (66% v 48%, P < or = .05). CR rates for good-risk and poor-risk MDS patients were similar (79% and 58%, respectively). Treatment was particularly effective in patients with poor-prognosis karyotypes and secondary MDS, producing CR rates of 63% and 69%, respectively. Medlan duration of CR was 32 weeks (41 weeks for MDS; 33 weeks for CMML). Median survival was 60 weeks for MDS patients and 41 weeks for CMML patients. Prospective analysis of response by International Prognostic Scoring System (IPSS) risk classification showed comparable CR rates among intermediate 1 (60%), Intermediate 2 (83%), and high-risk (56%) categories. Fever of undetermined origin and Infections occurred in 72% and 59% of patients, respectively. Six patients (10%) died during Induction therapy. This regimen was well tolerated and was associated with a low mortality rate.

High-dose Ara-C for remission induction and consolidation of previously untreated adults with ALL or lymphoblastic lymphoma.

Thirty-two patients with untreated ALL (n = 26) or lymphoblastic lymphoma (n = 6) between 17 and 65 years of age were treated with a short remission induction course with VP16-213, amsacrine, intermediate dose Ara-C for 6 days, prednisone and intrathecal methotrexate, followed by a consolidation course with vincristine, amsacrine, high dose Ara-C for 4 days, prednisone and intrathecal methotrexate. After subsequent cranial irradiation, no further maintenance was planned. However, some patients underwent an allogenic (n = 5) or autologous (n = 5) bone marrow transplantation after the consolidation treatment. Twenty-three of 32 patients (72%) achieved a complete remission. Ten of 13 patients with T-ALL or lymphoma, six of eight patients with pre-B or common ALL, and seven of 11 patients with B-ALL or Burkitt's lymphoma achieved a complete remission. The median duration of remission was 24 months. Overall survival for the whole group was 35% at 5 years. The disease-free survival was 45% at 5 years. Long-term survival for patients with B or T-ALL was approximately 60%, compared with 15% for those with common or pre B-ALL. Short term intensive courses including intermediate or high dose Ara-C during remission and consolidation treatment lead to results comparable to those obtained with long-term maintenance regimens. Our regimen may be sufficient for patients with T or B-ALL. Larger randomized studies are needed to investigate the relative importance of our observations.

Autologous peripheral stem cell transplantation of the blastic phase of chronic myeloid leukemia following sequential high-dose cytosine arabinoside and melphalan.

Blast-phase chronic myelogenous leukemia (CML) is the terminal phase in CML and is uniformly fatal. We treated 12 patients with blast-phase CML with a program of high-dose cytarabine 3.0 g/m2 and melphalan 140 mg/m2, followed by reinfusion of stem cells obtained from peripheral blood during the chronic phase. Seven patients achieved either a partial or complete hematologic remission, while five patients showed no response to therapy. One patient returned to chronic phase features with loss of a chromosomal abnormality acquired at blast phase, restoration of hematopoiesis, and a decrease in the amount of bone marrow blasts to less than 10%. Six patients cleared their peripheral blasts and showed recovery of their myeloid and platelet lineages, but all six required treatment for acceleration within 3 months. Of the five nonresponding patients, three died with aplastic bone marrow, one patient never cleared peripheral blasts after chemotherapy, and one patient had evidence of peripheral blasts 3 weeks after the autologous stem cell reinfusion. None of the patients returned to a normal karyotype. The ablative regimen was effective in eradicating bone marrow blasts to < 10% in 8 of 10 patients in whom interpretable bone marrow samples were performed following chemotherapy. Overall, the median survival for all patients from the time of stem cell reinfusion was 5.5 months. We conclude that autotransplants with peripheral blood can successfully be used to support hematopoiesis during high-dose therapy for CML blast crisis, however, has no role by itself in the curative therapy of blast crisis CML. A small number of patients can be restored to chronic phase features, and this may provide an opportunity to administer subsequent alternative treatments designed to eradicate the malignant stem cell population. Autotransplants with stem cells may also be used as therapy for patients without a histocompatible marrow donor. However, the autotransplant may be more effective when used during the chronic phase of CML, with the use of hematopoietic growth factors, and with reinfusion of stem cells depleted of the malignant Philadelphia chromosome-positive clone.

Low-dose cytosine arabinoside for treating hypocellular acute leukemia in the elderly.

Ten previously untreated elderly patients with hypocellular acute leukemia received a low dose of cytosine arabinoside (Ara-C), 10 mg/m2 injected subcutaneously every 12 hours for 14-28 days. Six patients achieved a complete remission (CR) for periods ranging for 6-23 months (median 8.5 months) and the others had a partial remission (PR). Relapse has occurred in three patients to date. The median survival ranged from 10-24 months (median 14.5 months). Only two of the six patients, in whom bone marrow biopsy was performed at CR, had a normal cellularity. This change, however, did not appear to be a significant prognostic factor in those patients. In seven patients who achieved a CR or PR low-dose Ara-C was administrated as maintenance therapy at the same low dose for 10 days each month. Treatment was well tolerated in all patients despite for myelosuppression. There were no drug-related deaths. These observations suggest that low-dose Ara-C is effective in treating elderly patients with hypocellular acute leukemia.