A comparison of bone marrow transplantation with maintenance chemotherapy for patients with acute nonlymphoblastic leukemia in first complete remission

Twenty patients treated with maintenance chemotherapy for acute nonlymphoblastic leukemia after achieving complete remission were compared with 13 patients who underwent bone marrow transplantation from an HLA-identical sibling. The median age was 27 years for both maintenance chemotherapy patients (range 17-42 years) and for patients undergoing bone marrow transplantation (range 16-42 years). The 1-year survival for maintenance chemotherapy was 80% vs. 54% with bone marrow transplantation (p = NS). Complete remission durability was 70% at 1 year for maintenance chemotherapy (34% projected for 5 years) compared with no relapses in the first year with bone marrow transplantation (p = 0.01). Patients on maintenance chemotherapy were hospitalized for an average of 22 days (range 0-171 days) during the first 12 months of treatment. Patients undergoing bone marrow transplantation were hospitalized for an average of 82 days (range 41-113 days) in the same time period. Severe hematologic toxicity was seen in 13/13 bone marrow transplantation patients and 6/20 maintenance chemotherapy patients. Chronic graft-vs.-host disease occurred in 3/7 surviving bone marrow transplantation patients. Maintenance chemotherapy had an average first year cost of +3,076.00 for patients who did not relapse and +48,827.00 for patients that relapsed. The first year costs for bone marrow transplantation averaged +84,102.00. Thus, maintenance chemotherapy was associated with a better early survival, less toxicity, and lower cost than bone marrow transplantation in the first year after initiating therapy. However, fewer relapses with bone marrow transplantation suggest that it will yield a higher long-term survival rate.     

Small-dose Harringtonine induces complete remission in patients with acute promyelocytic leukemia

Small-dose Harringtonine (1-3 mg infused during 4-5 hr) was used as a single agent to treat 10 patients with acute promyelocytic leukemia. Every patient received one to three courses, each lasting 13-81 days (mean 33 days). The interval between courses (i.e., interruptions) was 5-11 days. During treatment, marrow aplasia occurred in one patient and hypoplasia in three. Pancytopenia occurred in all 10 patients. Complete remission was achieved in seven patients (70%) and cytoreduction in two. In vitro studies showed that, although Harringtonine produced a decrease in leukemic cells in all five series of marrow cultures from five patients, there was only one wherein the decrease was accompanied by a simultaneous absolute increase in differentiated myeloid cells. Considerable discrepancy existed between the culture results and clinical responses. These results seem to suggest that the therapeutic effect of Harringtonine on acute promyelocytic leukemia originates chiefly from cytotoxicity.     

Management of adult patients with acute lymphoblastic leukemia in first complete remission

BACKGROUND:

The optimal postremission therapy in adults with acute lymphoblastic leukemia (ALL) is still a matter of debate. The objective of this study was to compare the various potential therapeutic options for patients who achieved first complete remission.

METHODS:

The authors conducted a systematic review and meta‐analysis of randomized trials, including patients with standard‐risk (SR) All and high‐risk (HR) ALL who received first postremission therapy. Outcomes assessed were all‐cause mortality (ACM), disease recurrence (relapse), and nonrelapse mortality (NRM). Relative risks (RRs) with 95% confidence intervals (CIs) were estimated and pooled.

RESULTS:

Overall, there was a significant reduction in ACM in the allogenic stem cell transplantation (alloSCT) arm (RR, 0.88; 95% CI, 0.8‐0.97) compared with autologous stem cell transplantation (ASCT) or chemotherapy. Subgroup analyses revealed a similar pattern among SR patients (RR, 0.8; 95% CI, 0.68‐0.94) but a nonsignificant advantage for alloSCT among HR patients (RR, 0.88; 95% CI, 0.76‐1.01). There was an increase in NRM (RR, 2.99; 95% CI, 1.37‐6.53) and a decrease in the relapse rate in the alloSCT arm (RR, 0.52; 95% CI, 0.33‐0.83). There was no difference in ACM or the relapse rate between the ASCT and chemotherapy arms.

CONCLUSIONS:

Overall, alloSCT was superior to ASCT or chemotherapy for patients with ALL in first complete remission. The survival advantage was of greater statistical significance for patients with SR ALL than for patients with HR ALL. Cancer 2010. © 2010 American Cancer Society.     

CAMAL: a new prognostic marker for remission in acute nonlymphoblastic leukemia

A leukemia-associated antigen, CAMAL, shown to be present in bone marrow (BM) cells from patients with acute nonlymphoblastic leukemia (ANLL) even during remission, has been examined using indirect immunoperoxidase and a monoclonal antibody, CAMAL-1. We are ending the third year of an ongoing blind study designed to monitor the number of BM cells expressing the CAMAL protein (CAMAL BM value) in ANLL patients over the course of their disease. Results thus far have revealed that the CAMAL BM value in individual patients often changed significantly post-chemotherapy. This change appeared to be a useful prognostic marker in many instances. ANLL patients at initial presentation whose CAMAL BM values increased or stayed the same post-chemotherapy had significantly (p less than 0.025) shorter remission lengths (x = 6.8 months, n = 24) than those whose CAMAL BM values decreased (x = 19.2 months, n = 10). There are indications that increasing CAMAL BM values during remission occur prior to clinical relapse.     

Duration of second complete remission compared with first complete remission in patients with acute myeloid leukemia. Eastern Cooperative Oncology Group.

The prognosis for patients with acute myeloid leukemia in first relapse is generally poor. The ability to induce a second complete remission (CR) with the same chemotherapy used in initial induction therapy is limited. Remission inversion rate, defined as achieving a longer second CR than the first CR in response to standard chemotherapy for relapse, is important in assessing studies of novel chemotherapy or immunologic treatment strategies for patients with relapsed disease. One hundred and twenty-four patients entered on two Eastern Cooperative Oncology Group (ECOG) studies for patients with relapsed AML were analyzed to determine the remission inversion rate. Twenty-two of the 124 patients (18%; 95% confidence interval 12-26%) experienced a longer second CR duration than the first CR duration by at least 2 months. Inversion of CR duration is thus not a rare event. The inversion frequency reported here establishes a baseline upon which future studies in relapsed disease need to be defined.     

The monocyte tumor necrosis factor-alpha production in patients with acute leukemia in complete remission

Tumor necrosis factor-α (TNF-α) production by unstimulated and lipopolysaccharide (LPS)-stimulated peripheral monocytes has been studied in 17 acute myeioid leukemia (AML) patients, 54 AML patients in complete remission (AML-CR), 9 acute lymphoblastic leukemia (ALL) patients and 13 ALL patients in complete remission (ALL-CR). TNF-α production by the unstimulated monocytes in ALL patients (n - 6, mean: 6.6 ± 4.9 u/ml) was higher than that of normal controls (n = 13, 0.9 ± 0.7 u/ml), AML patients (n = 14, 2.0 ± 2.1 u/ml) and AMLCR patients (n = 21,1.4 ± 1.2 u/ml). TNF-α production by the LPS-stimulated monocytes of the AML-CR patients (n = 54,12.4 ± 13.4 u/ml) was significantly higher than that of the normal controls (n = 21, 3.5 ± 2.5 u/ml) and the AML patients (n = 17, 2.6 ± 2.4 u/ml),p < 0.01, but there were not any significant differences among the AML-CR patients and the ALL patients or the ALL-CR patients. We separated the AML-CR patients into 3 groups, depending on the length of their remission, and found that AML-CR patients with longer than 6 months (M) but less than 60 M (n = 21,15.7 ± 16.9 u/ml) and the patients with a remission longer than 60 M (n = 11,18.2 ± 15.9 u/ml) had significantly higher TNF-α production than that of the controls.     

Potential cure of acute myeloid leukemia : analysis of 1069 consecutive patients in first complete remission

BACKGROUND: Potential cure of acute myeloid leukemia (AML) is now a widely accepted idea, but it is uncertain whether there is heterogeneity in the failure rate in patients once they have been in complete remission (CR) for various periods of time. METHODS: The long-term outcomes were analyzed in 1069 consecutive AML patients in first CR who were diagnosed and treated at the University of Texas M. D. Anderson Cancer Center between 1991 and 2003. RESULTS.: The failure rates as yearly risk of treatment failure were 69.1 in the first year, 37.7 in the second year, 17.0 in the third year, 7.6 in the fourth year, and 6.6 in the fifth year, suggesting that 3 years from the CR date is a convenient time to consider patients potentially cured. The effect of cytogenetics on relapse-free survival (RFS) remained constant throughout the first 3 years, whereas the effect of age increased with time. The probability of RFS for patients alive without disease recurrence at 3 years was 84.0% at 6 years. When the interaction between age and cytogenetics was examined for these patients, the outcomes of those with favorable cytogenetics were found to be excellent regardless of age. However, in the intermediate cytogenetic group, although patients aged <60 years had excellent outcomes, those aged > or =60 years were found to be at a substantial risk of disease recurrence even after 3 years of CR, with a 6-year RFS rate of 56.5%. There were only 6 patients with adverse cytogenetics in this cohort. CONCLUSIONS: The results of the current study demonstrate that the risk of treatment failure differs over time according to a combination of cytogenetics and age.     

Marrow transplantation for acute nonlymphoblastic leukemia in first remission using fractionated or single-dose irradiation

Fifty-three patients with acute nonlymphoblastic leukemia in first remission were treated with cyclophosphamide, total body irradiation and marrow transplantation. Twenty-seven patients received 1000 rad in one exposure and 12 are living in remission 6–29 months later. Twenty-six received 200 rad on each of 6 days and 18 are living in remission after 4–27 months. Kaplan-Meier analysis shows a survival advantage for the fractionated regimen (p = 0.05).     

High-dose cytosine arabinoside therapy with and without anthracycline antibiotics for remission reinduction of acute nonlymphoblastic leukemia

Seventy-eight patients with acute nonlymphoblastic leukemia in relapse were treated with high-dose cytosine arabinoside (3 g/m2 intravenously (IV) every 12 hours for 12 doses) alone, or with three days of anthracycline antibiotics (doxorubicin 20 mg/m2 or daunorubicin 30 mg/m2 IV daily) after completing the course of cytosine arabinoside. Consolidation and maintenance therapy was not given. When anthracyclines were added there was no increase in frequency or severity of nonhematologic toxicity including conjunctivitis, photophobia, dermatitis, cerebellar dysfunction, and gastrointestinal disturbance. All 78 patients achieved aplasia of the bone marrow. Five patients in each group died before bone marrow recovery. The use of anthracyclines did not prolong bone marrow recovery, with both groups demonstrating adequate granulocyte and platelet counts about four weeks after beginning treatment. Forty-one (53%) of the total 78 patients achieved a complete remission. In patients not clinically resistant to conventional-dose cytosine arabinoside, both regimens were equally effective inducing a complete remission (high-dose cytosine arabinoside alone, 12/19 [63%]; with anthracycline, 11/17 [65%], P = .270); in patients clinically resistant, the regimen including anthracycline was superior (15/27 [56%] v 3/15 [20%], P = .022). The duration of unmaintained response was similar (median, five months), but the longest remissions occurred when anthracyclines were used. Thus, high-dose cytosine arabinoside is effective in producing remissions in relapsed patients with acute nonlymphoblastic leukemia, and the addition of an anthracycline enhances this effect.     

Independent prognostic impact of CD15 on complete remission achievement in patients with acute myeloid leukemia

The prognostic role of CD15 in acute myeloid leukemia (AML) has been tested in different studies with conflicting results. To address this issue, we retrospectively evaluated a cohort of 460 AML patients of all ages with the exclusion of acute promyelocytic leukemia (M/F 243/217, median age 50.6 years [range 0.9‐81.2]) intensively treated at our institute between January 1999 and December 2010. CD15 positivity was found in 171 of 406 evaluable patients (42.1%). Complete remission (CR) was achieved by 334 patients (72.6%), while 82 (17.8%) were resistant and 44 (9.6%) died during induction: the median CR duration was 15.5 months (range 0.6‐176.0), with 2‐year disease‐free survival rate of 45.1% (95% confidence interval 39.6‐50.6). The median overall survival was 14.4 months (range 0.3‐177.0), with 2‐year overall survival rate of 42.2% (95% confidence interval 37.5‐46.9). At univariate analysis for CR achievement, age < 60 years (P < .001), World Health Organization classification (P = .045), low‐risk karyotype (P < .001), no high‐risk karyotype (P = .006), positivity for AML‐ETO (P = .004)/CBFβ‐MYH11 (P = .003)/CD15 (P = .006)/CD11b (P = .013), negativity for FLT3‐ITD (P = .001), Hb > 8 g/dL (P = .020), and white blood cell < 50 × 10⁹/L (P = .034) had a favorable impact. At a multivariate logistic regression model, CD15 positivity (P = .002), age < 60 years (P = .008), white blood cell < 50 × 10⁹/L (P = .017), and low‐risk/no high‐risk karyotype (P = .026/P = .025) retained an independent prognostic role on CR achievement . The baseline assessment of CD15 positivity appears to have a role in the risk evaluation for CR achievement in AML patients undergoing intensive chemotherapy and should be assessed in prospective studies together with other clinical and biologic features already reported.     

急性早幼粒细胞白血病缓解后治疗方案的疗效分析

目的：探索更有效的急性早幼粒细胞白血病（acute promyelocyte leukemia,APL）缓解后的治疗方案。方法：初治APL患者应用全反式维甲酸（all-trans retinoic acid,ATRA）诱导分化,达到完全缓解（complete response,CR）的50例患者分为2组,采取不同的缓解后治疗方案：复方黄黛片和化疗交替组（A组,23例）;ATRA和化疗交替组（B组,27例）,比较2种缓解后治疗方案的远期疗效。结果：50例患者中复发8例,A组1/23例（4.3%）,B组7/27例（25.9%）,差异有统计学意义（P=0.038）。远期疗效A组明显优于B组（3年无病生存率分别为100%和79%,5年无病生存率分别为91%和58%,P=0.023）。结论：复方黄黛片与化疗交替为一种理想的APL缓解后治疗方案,疗效优于ATRA与化疗交替组。     

Minimal residual disease in childhood acute lymphoblastic leukemia: analysis of patients in continuous complete remission or with consecutive relapse.

Differences in tumor cell burden among acute lymphoblastic leukemia (ALL) patients are largely unexplored, because methods of detecting residual malignant cells have not been sufficiently sensitive. Using the polymerase chain reaction (PCR) amplification of rearranged T-cell receptor delta(TCR delta)-chain junctional sequences for the preparation of clonospecific probes, we performed a retrospective PCR study of remission bone marrow (BM) samples in seven pediatric patients with ALL who subsequently relapsed (the largest series studied so far) and in 10 patients who were in longterm (greater than 39 to greater than 72 months) remission. Following two rounds of PCR primed by nested amplimers, 1 x 10(-4) to 1 x 10(-6) cells could be identified in 16 out of 17 cases. PCR analysis of 39 BM and peripheral blood samples obtained from ALL patients considered to be in complete remission according to morphological criteria revealed the following results. In BM remission specimens of all 10 patients in continuous complete remission for a long time (median 55 months), no residual leukemic cells could be identified in the latest remission sample available for PCR analysis. In three patients the persistence of residual leukemic cells, or the continuous increase of residual blasts to the point of clinical manifestation, were indicative of impending relapse. In three patients PCR analysis failed to identify residual leukemic cells in BM samples obtained 2, 6 and 16 months respectively before clinical relapse. Differences in the duration of minimal residual disease were not associated with distinct clinical-hematological features. In one patient a different pattern of V delta 2 recombination occurred in leukemic cells from diagnosis to relapse, thus preventing the further monitoring of the patient by the initial clonospecific probe.     

A pilot study of interleukin-2 for adult patients with acute myelogenous leukemia in first complete remission

BACKGROUND: Interleukin-2 (IL-2) has immunomodulatory effects, including stimulating the activity of cytotoxic T cells and natural killer cells, and inducing the generation of lymphokine-activated killer cells. The authors investigated whether IL-2 may improve the duration of complete remission (CR) and survival in acute myelogenous leukemia (AML) patients in first CR. METHODS: Eighteen patients were included after achieving a CR and receiving at least two courses of consolidation chemotherapy. Therapy was comprised of IL-2 4.5 x 10(5) U/m2 daily by continuous infusion (CI) for 12 weeks, plus boluses of 1 x 10(6) U/m2 on Day 8 and weekly thereafter while continuing the CI. No further chemotherapy was given after the administration of IL-2 was started. RESULTS: The median age of the patients was 50 years (range, 18-73 years), and 7 patients (39%) had an antecedent hematologic disorder (AHD). The median CR duration was 12 months, with 6 patients still alive in CR at a median follow-up of 64 months (range, 50-82 months). Long term CR by cytogenetics occurred in 2 of 5 patients with a normal karyotype (CR duration of 68+ months and 72+ months, respectively), 1 of 3 patients with t(8;21) (CR duration of 82+ months), 1 patient with inv(16) (CR duration of 67+ months), none of 2 patients with -5/-7 (1 patient died in CR after 10 months), 1 of 2 patients with abnormalities in chromosome 11 (CR duration of 60+ months), and 1 of 4 patients with miscellaneous abnormalities (CR duration of 74+ months). The median survival was 47 months. To assess the significance of these results, the authors selected two historic controls receiving long term postremission chemotherapy per each IL-2 case. The controls had remained in CR for at least as long as the cases when the latter underwent treatment initiation with IL-2 and were matched for the number of induction courses required to achieve CR, AHD, cytogenetic abnormalities, and age. Six of 18 IL-2 patients (33%) were alive in CR at 3 years compared with 7 of 36 controls (19%) (P = 0.31). Nine IL-2 patients (50%) were alive at 3 years compared with 10 controls (28%) (P = 0.13). CONCLUSIONS: These results suggest that IL-2 is tolerable in AML patients in first CR and should be studied further in future studies as a therapeutic strategy to prolong remission duration.     

Monitoring the remission induction therapy of acute nonlymphoblastic leukemia by bone marrow cell culture criteria

In 31 cases of acute nonlymphoblastic leukemia, bone marrow cells were serially cultured in semi-solid agar during the remission induction therapy. A normal in vitro cell growth pattern returned in 15 out of 22 patients up to 77 days before a complete remission was established by clinical and hematological criteria. In 6 cases the return of normal colonies coincided with clinical and hematological evidence of a complete remission. Nine patients failed to attain a remission and died from complications of bone marrow aplasia. Only one had a normal number of colonies and a normal cluster/colony ratio in cultures prepared 11 days after the completion of the first course of chemotherapy. At this time, his platelet count increased to normal level, possibly indicating a developing remission. Bone marrow cell culture criteria are useful in monitoring the remission induction therapy in patients with acute nonlymphoblastic leukemia. An early return of normal in vitro cell growth pattern suggests an approaching remission, which may be achieved several weeks later.     

Chemotherapy for patients with acute myeloid leukemia in first remission

Although the majority of patients with acute myeloid leukemia (AML) achieve a complete remission with induction chemotherapy, most will ultimately relapse. Therefore, the optimal postremission therapy for AML remains to be defined, and further improvements in treatment strategies are required. Clinical trials have demonstrated that early intensive consolidation therapy with high-dose cytarabine can produce prolonged responses in up to 40% of patients in remission after standard induction therapy. Equally, however, it has been shown that high-dose cytarabine used in induction therapy can deliver equivalent long-term results. Autologous and allogeneic stem cell transplantation in first remission are also valid alternatives, but the value of low-dose maintenance treatment seems confined to acute promyelocytic leukemia. Further improvement in the treatment of AML is likely to depend on the development of new strategies, such as molecularly targeted or immune therapies.