Phase II study of chemotherapy and stem cell transplantation for adult acute lymphoblastic leukemia or lymphoblastic lymphoma: Japan Clinical Oncology Group Study 9004

Granulocyte colony-stimulating factor (G-CSF)-supported, post-remission chemotherapy (Cx) for adult acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) was evaluated. One hundred and forty-three eligible patients (median age, 41 years) including 126 ALL and 17 LBL receiving induction Cx (vincristine, cyclophosphamide, prednisolone [PSL], doxorubicin, L-asparaginase, intrathecal-methotrexate [IT-MTX]) were analyzed. For patients achieving complete response (CR), two courses of post-remission Cx (course A of daunorubicin, cytosine arabinoside, vindesine, PSL plus IT-MTX; course B of mitoxantrone, etoposide, vincristine, PSL plus IT-MTX) with the use of G-CSF were repeated alternately; thereafter, maintenance Cx including MTX and 6-mercaptopurine was given for 2 years. One hundred and nineteen (83%) patients achieved CR, while 14 (10%) died during induction. Among the 119 patients achieving CR, five died in remission, 76 relapsed, and the remaining 38 were alive without disease. The median survival time of the 143 eligible patients was 26 months (95% confidence interval, 19-34). At a median follow-up time of 9 years, the 5-year survival rate was 32% and the 5-year progression-free survival (PFS) rate was 26%. The 5-year survival rate of 36 patients who underwent autologous (n = 20) or allogeneic stem cell transplantation (SCT; n = 16) in the first CR group was 58%. Compared with the authors' previous trials, survival and PFS were markedly improved. In conclusion, G-CSF-supported, intensive post-remission Cx and subsequent SCT are worthy of further investigation for the treatment of adult ALL and LBL.     

Comparison of the L10M consolidation regimen to an alternative regimen including escalating methotrexate/L-asparaginase for adult acute lymphoblastic leukemia: a Southwest Oncology Group Study.

The effectiveness of intensive post-remission chemotherapy regimens for adult patients with acute lymphoblastic leukemia (ALL) is limited by both a high rate of disease recurrence and a substantial incidence of treatment toxicity. To evaluate a potentially more effective and less toxic approach, we conducted a multicenter phase III trial of consolidation therapies comparing the standard L10M regimen with one combining the brief, intensive L17M regimen and escalating methotrexate (MTX) and L-asparaginase (L-asp). Patients over age 15 with previously untreated ALL were eligible. Induction therapy included vincristine, prednisone, doxorubicin, cyclophosphamide and intrathecal methotrexate administered over 36 days. Patients who achieved complete remission (CR) were randomized to receive consolidation with either the L10M regimen or with DAT (daunomycin, cytosine arabinoside, 6-thioguanine) and escalating MTX and L-asp. The randomization was stratified by age, WBC and Ph chromosome status. Maintenance therapy was the same in both arms. Of 353 eligible patients, 218 (62%) achieved CR and 195 were randomized. The treatment arms did not differ significantly with respect to disease-free survival (DFS; P= 0.46) or overall survival (P= 0.39). Estimated DFS at 5 years was 32% (95% confidence interval (CI) 23-42%) in the L10M arm and 25% (95% CI 16-33%) in the DAT/MTX/L-asp arm. In each arm, 4% of patients died of toxicities (infection in all but one case). Infections and nausea/vomiting were somewhat more common in the L10M arm (occurring in 68% and 53% of patients respectively) than the DAT/MTX/L-asp arm (56% and 33%). The DAT/MTX/L-asp consolidation regimen was associated with some reduction in nonfatal toxicities, but no significant improvement in DFS, overall survival or non-relapse mortality when compared to the standard L10M regimen.     

Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial.

PURPOSE: We analyzed the benefits of a risk-adapted postremission strategy in adult lymphoblastic leukemia (ALL), and re-evaluated stem-cell transplantation (SCT) for high-risk ALL. PATIENTS AND METHODS: A total of 922 adult patients entered onto the trial according to risk groups: standard-risk ALL (group 1), high-risk ALL (group 2), Philadelphia chromosome-positive ALL (group 3), and CNS-positive ALL (group 4). All received a standard four-drug/4-week induction course. Patients from group 1 who achieved a complete remission (CR) after one course of induction therapy were randomly assigned between intensive and less intensive postremission chemotherapy, whereas those who achieved CR after salvage therapy were then included in group 2. Patients in groups 2, 3, and 4 with an HLA-identical sibling were assigned to allogeneic SCT. In groups 3 and 4, autologous SCT was offered to all other patients, whereas in group 2 they were randomly assigned between chemotherapy and autologous SCT. RESULTS: Overall, 771 patients achieved CR (84%). Median disease-free survival (DFS) was 17.5 months, with 3-year DFS at 37%. In group 1, the 3-year DFS rate was 41%, with no difference between arms of postremission randomization. In groups 2 and 4, the 3-year DFS rates were 38% and 44%, respectively. In group 2, autologous SCT and chemotherapy resulted in comparable median DFS. Patients with an HLA-matched sibling (groups 2 and 4) had improved DFS. Three-year DFS was 24% in group 3. CONCLUSION: Allogeneic SCT improved DFS in high-risk ALL in the first CR. Autologous SCT did not confer a significant benefit over chemotherapy for high-risk ALL.     

Allogeneic bone marrow transplantation for adult acute lymphoblastic leukemia: a single-centre experience.

Between 1990 and 1997, we performed 29 allogeneic BMTs for acute lymphoblastic leukemia (ALL) patients with HLA-identical sibs. Their median age was 31 years (range 15 to 43); there were 15 males and 14 females. The conditioning protocol was Cy-TBI (n = 15), VP16-Cy-TBI(n = 12), CBV (n = 1) and Bu-Cy (n = 1). Cyclosporin and methotrexate were used for GVHD prophylaxis. The median disease-free survival (DFS) was 12 months (range 1 to 92) with an actuarial 4-years DFS of 42.3 per cent. Three patients died of transplant-related complications before 100 days. Relapse occurred in 11 cases at a median time of 5 months (range 3 to 14). All nine patients relapsing within one year died form resistant leukemia. Three patients died of late treatment-related complications. There were 13 survivors (median follow-up 38 months, range 12-98), with 12 in remission. Only four had limited cGVHD, and all had 100 per cent performance scores. One patient also cleared her chronic hepatitis B carrier status due to acquired immunity. The DFS rates amongst CR1 cases and R1/CR2 cases were comparable (p = 0.39). No long-term DFS is obtained from patients with resistant disease (n = 4). The survival results for BMT at CR1 were superior to those using intensive chemotherapy consolidation (p = 0.29), mainly due to poor late results in the chemotherapy arm. For young ALL patients with HLA-matched siblings, the option of BMT should be considered in light of local consolidation survival results.     

Hyper-CVAD方案治疗淋巴母细胞淋巴瘤

 目的　观察Hyper-CVAD方案对淋巴母细胞淋巴瘤（LBL）的疗效及其毒副作用。方法　2003年11月至2006年12月收治LBL患者40例,其中20例接受Hyper-CVAD／MA方案交替治疗8个疗程;另20例予常规急性淋巴细胞白血病方案,包括VDCLP、CAT、HD-MTX、EA等方案交替治疗,后予维持治疗。结果　Hyper-CVAD方案组：诱导化疗结束后CR18例（90 ％）,PR2例（10 ％）,总有效率100 ％,3年无病生存率（DFS）55 ％,总体生存率（OS）66 ％。常规急淋方案组：诱导化疗结束后CR17例（85 ％）PR1例（5 ％）,PD2例（10 ％）,总有效率90 ％,3年DFS 35 ％,OS 52 ％。两组患者在诱导期的CR率和有效率差异无统计学意义。3年DFS和3年OS的差异均有统计学意义（P＜0.05）。结论　Hyper-CVAD方案可以提高LBL患者的长期无病生存率,可作为LBL一线治疗方案之一。     

Induction therapy by frequent administration of doxorubicin with four other drugs, followed by intensive consolidation and maintenance therapy for adult acute lymphoblastic leukemia: the JALSG-ALL93 study.

In order to improve the disappointing prognosis of adult patients with acute lymphoblastic leukemia (ALL), we applied similar induction therapy as that used for acute myeloid leukemia (AML), ie frequent administration of doxorubicin (DOX). DOX 30 mg/m(2) was administered from days 1 to 3 and from days 8 to 10 together with vincristine, prednisolone, cyclophosphamide and L-asparaginase, followed by three courses of consolidation and four courses of intensification. From December 1993 to February 1997, 285 untreated adult patients with de novo ALL were entered. Of 263 evaluable patients (age 15 to 59; median 31), 205 (78%) obtained complete remission (CR). At a median follow-up period of 63 months, the predicted 6-year overall survival (OS) rate of all patients was 33%, and disease-free survival (DFS) rate of CR patients was 30%, respectively. By multivariate analysis, favorable prognostic factors for the achievement of CR were age <40 and WBC <50 000/microl; for longer OS were age <30 and WBC <30 000/microl; and for longer DFS of CR patients were FAB L1 and ALT <50 IU/l. Among 229 patients who had adequate cytogenetic data, 51 (22%) had Philadelphia (Ph) chromosome. Ph-negative chromosome was a common favorable prognostic factor for CR, longer OS and DFS. DFS was not different between early sequential intensification (n = 48) and intermittent intensification (n = 43) during the maintenance phase. Among CR patients under 40 years old, the 6-year survival was not different between the allocated related allo-BMT group (34 patients) and the allocated chemotherapy group (108 patients). However, among patients with Ph-positive ALL, the survival of patients who actually received allo-BMT was superior to that of patients who received chemotherapy (P = 0.046).     

Pattern of disease recurrence and prognostic factors in patients with osteosarcoma treated with contemporary chemotherapy

BACKGROUND: The goal of the current study was to define the clinical features and outcome of recurrent osteosarcoma (OS) in children and young adults initially treated with contemporary chemotherapy. METHODS: The authors reviewed the clinical features, therapy, and outcome for 59 patients from the Mayo Clinic (Rochester, MN) and Children's Hospital and Regional Medical Center (Seattle, WA). They were diagnosed initially with OS between January 1990 and December 2000, received multiagent chemotherapy (most frequently cisplatin, doxorubicin, high-dose methotrexate, and ifosfamide), and developed disease recurrence after achieving an initial complete response (CR). RESULTS: The most common site of initial disease recurrence was the lung only (n = 36 patients), followed by distant bone (n =8 patients), combined lung and other sites (n =7 patients), and other sites (n =8 patients). The median time to first disease recurrence was 15 months (range, 2-92 months) from the initial diagnosis. Thirty patients with isolated pulmonary recurrence achieved a second CR, either with surgery alone (n =15 patients) or surgery and salvage chemotherapy (n =15 patients). For this group, the 4-year disease-free survival (DFS) and overall survival rates were 7% (95% confidence interval [95% CI], 0-16%) and 28% (95% CI, 11-45%), respectively. For all 59 patients with recurrent OS, the 4-year DFS and overall survival rates were 6% (95% CI, 0-12%) and 23% (95% CI, 10-36%), respectively. The only factors associated with improved DFS and overall survival rates were unilateral pulmonary recurrence, solitary pulmonary nodule at recurrence, more than 24 months between the initial diagnosis and first disease recurrence, and achievement of a second CR. CONCLUSIONS: The DFS and overall survival rates for recurrent OS after contemporary therapy remained poor even for patients with isolated pulmonary recurrence. Therefore, new treatment strategies are needed.     

成人急性白血病强化治疗67例预后分析

目的：观察成人急性白血病（ＡＬ） 患者完全缓解（ＣＲ） 后强化治疗的效果。方法：对６７ 例ＣＲ后的成人ＡＬ患者进行强化治疗,急性髓细胞性白血病（ＡＭＬ）以中剂量阿糖胞苷（ＩＤ－ Ａｒａ－ Ｃ）方案为主,急性淋巴细胞性白血病（ＡＬＬ）以中剂量氨甲蝶呤（ＩＤ－ ＭＴＸ）方案为主。结果：４８ 例ＡＭＬ患者中位ＣＲ 期１６ 个月,预期３ 年和４ 年无病生存（ＤＦＳ）为３６９％ 和２１１ ％ ;２３ 例（４７９ ％） 患者复发。１９ 例ＡＬＬ 患者中位ＣＲ 期１４ 个月,预期４ 年ＤＦＳ 为３１５％ ;１０ 例（５２６％ ） 患者复发。结论：以ＩＤ－ Ａｒａ－ Ｃ 为主的强化方案及以ＩＤ－ ＭＴＸ 为主的强化方案分别能延长ＡＭＬ及ＡＬＬ患者的ＤＦＳ,降低复发率     

Prognosis and treatment of lymphoblastic lymphoma in adults: a report on 80 patients.

PURPOSE: We analyzed prognostic factors in 80 adult patients with lymphoblastic lymphoma (LBL). PATIENTS AND METHODS: Twenty-one patients received six monthly courses of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and maintenance chemotherapy for 12 months. The LNH-84 protocol (30 patients) consisted of four courses of high-dose CHOP followed by consolidation for 4 months. Both FRALLE (22 patients) and LALA (seven patients) protocols were two intensive chemotherapy regimens for acute lymphoblastic leukemia (ALL) that included an induction with daunorubicin, vincristine, cyclophosphamide, prednisolone (and asparaginase for the FRALLE regimen), consolidation, and maintenance chemotherapy that lasted for 2 years. RESULTS: Sixty-six patients (82%) achieved a complete remission (CR). The CR duration rate and overall survival rate at 30 months were estimated to be 46% and 51%, respectively, with a median follow-up of 55 months. Only two of 37 relapses occurred after 26 months. Chemotherapy protocol did not influence CR rate, CR duration, and survival. A higher CR rate was associated with an age of less than 40 years, lactic dehydrogenase (LDH) level of less than two times the upper limits of normal, and no or one extranodal site of disease. Short survival was associated with a failure to achieve CR, age older than 40 years, B symptoms, LDH level more than two times the upper limits of normal, and hemoglobin level of less than 100 g/L. Bone marrow involvement had no prognostic value. We could not evaluate precisely the prognostic value of Ann Arbor stage because inclusion criteria differed among treatment groups. CONCLUSION: Our findings suggest that age and LDH are two important pretreatment prognostic factors for adult LBL, and that the optimal prognostic staging system remains a controversial issue.     

Role of Allogeneic HCT as Postremission Therapy for Transplant-Eligible Adult Lymphoblastic Leukemia/Lymphoma After Frontline Hyper-CVAD

BackgroundHyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with cytarabine and methotrexate (hyper-CVAD) is a commonly used regimen in adults with acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL). Adult patients fit for pediatric-inspired protocols have an excellent outcome with chemotherapy alone. However, it is unclear whether patients receiving hyper-CVAD should undergo allogeneic hematopoietic cell transplantation (HCT) as postremission therapy. Our aim was to examine the role of HCT at first complete remission (CR1) in adult ALL/LBL after hyper-CVAD.Patients and MethodsAdult patients with newly diagnosed ALL/LBL receiving frontline hyper-CVAD from 2008 to 2018 were identified and records retrospectively extracted.ResultsA total of 85 patients were identified and included for further analysis. The median (range) age was 23 (14-68) years, and 56 (66%) were male. A total of 24 (28%) had adverse cytogenetics, and 48 (56%) had at least one risk factor. All patients received hyper-CVAD as induction; induction failure was seen in 10 (12%). A total of 38 patients continued the hyper-CVAD course, while the remaining 47 received HCT in CR1. Three-year event-free survival (EFS) and overall survival for the entire cohort were 51.4% and 61.6%, respectively. Median follow-up of alive patients was 39.9 (3.8-123.8) months. At multivariable analysis for EFS, induction failure was associated with worse outcome (hazard ratio [HR], 4.8; 95% confidence interval [CI] 1.7-13.7; P = .003), whereas HCT in CR1 improved outcome (HR, 0.42; 95% CI 0.18-0.97; P = .044). Furthermore, HCT in CR1 was the only prognostic factor for overall survival (HR, 0.3; 95% CI 0.11-0.85; P = .023).ConclusionHCT at CR1 resulted in a favorable EFS and overall survival in ALL/LBL patients after hyper-CVAD frontline therapy. Given that hyper-CVAD is a widely used protocol for adult patients, further examination of this observation is warranted.     

Total body irradiation, thiotepa, and cyclophosphamide as a conditioning regimen for children with acute lymphoblastic leukemia in first or second remission undergoing bone marrow transplantation with HLA-identical siblings.

PURPOSE: Allogeneic hematopoietic stem-cell transplantation (HSCT) from HLA-identical siblings can be used to treat children with acute lymphoblastic leukemia (ALL). However, a significant proportion of patients with ALL who undergo HSCT relapse. For this reason, we prospectively evaluated a preparative regimen that included total body irradiation (TBI), thiotepa (TT), and cyclophosphamide (CY) in patients with high-risk ALL in first complete remission (CR) and in children with ALL in second CR. PATIENTS AND METHODS: Forty children (median age, 9 years; range, 1 to 18 years) with ALL in first or second CR who underwent allogeneic HSCT from HLA-identical siblings were conditioned with a combination of fractionated TBI, TT (10 mg/kg), and CY (120 mg/kg over 2 days). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine administered intravenously at a dose of 1 to 3 mg/kg/d for the first 21 days and subsequently orally at a dose of 6 mg/kg/d. RESULTS: All assessable patients were engrafted, with a median time of 11 and 24 days for neutrophil and platelet recovery, respectively. The preparative regimen was well tolerated. Only one patient died as a result of regimen-related causes. Eight patients relapsed at a median time of 8 months after transplantation (range, 3 to 9 months), and this determined a cumulative probability of relapse of 23%. Twenty-six of 40 patients (65%) are alive and in complete hematologic remission, with a median observation time of 36 months (range, 14 to 57 months), which results in a disease-free survival (DFS) at 3 years of 65%. The 13 patients who underwent transplantation in first CR had a DFS of 85%, whereas the 27 patients who underwent HSCT in second CR had a DFS of 56%. CONCLUSION: These data suggest that TT is an effective cytotoxic drug that can be safely added to the classical TBI-CY regimen. Because of its cell cycle-independent action, good CNS diffusion, and limited extramedullary toxicity, TT may contribute to increasing the percentage of children with ALL who are successfully cured with allogeneic BMT.     

Role of induction chemotherapy and bone marrow transplantation in adult lymphoblastic lymphoma: A report on 62 patients from a single center

Objective: To describe the outcome of an unselected large series ofpatients with lymphoblastic lymphoma (LBL) treated in a single institution.Patients and methods: Sixty-two patients were treated between 1980 and1992. Induction chemotherapy (CT) to achieve complete response (CR) was:French Multicenter Acute Lymphoblastic Leukemia (ALL) protocols (38),non-Hodgkins Lymphoma (NHL) protocols (20). Thirty patients underwenttransplant after achieving CR (allogeneic 12; autologous 18).Results: Forty-six patients (74%) achieved CR and 16 (26%)failed to respond. The patients who received an ALL induction had an89% CR rate, while the CR rate was 52% in patients whoreceived a NHL-like regimen. With a median follow-up of 93 months (range36–187), the actuarial overall survival (OS) rate for all patients is49% at five years and 41% at 10 years, and the actuarialevent-free survival (EFS) rate is 45% and 37%. OS and EFS inthe grafted population are, respectively, 60% and 56% at fiveyears. Our results also show a trend toward a longer OS in allograftedgroup.Conclusions: ALL induction therapy is more effective than the NHL-likeregimen for augmenting the CR rate. Autologous or allogeneic transplantationshould be considered as consolidation therapy in high-risk group patients.     

Outcomes of adult patients with relapsed acute lymphoblastic leukemia following frontline treatment with a pediatric regimen

We analyzed the outcome of 46 patients with acute lymphoblastic leukemia (ALL) who relapsed following treatment with a pediatric-based protocol; 34 received intensive re-induction chemotherapy, with a CR2 rate of 62%, median overall survival (OS) 7.8 months, median relapse-free survival 5.2 months and one year OS 19%. Allogeneic HSCT was performed in 8 patients in CR2/3, with a median OS 2.2 months. OS was superior in patients who relapsed after completion of chemotherapy, compared to those relapsing on treatment. The outcome of adult ALL relapsing after treatment was therefore poor, and novel salvage strategies are needed to improve outcomes.     

Treatment of adult patients with acute lymphocytic leukemia in relapse

Thirty-eight patients with a diagnosis of relapsed acute lymphocytic leukemia were accrued to a treatment program of reinduction therapy by the Eastern Cooperative Oncology Group (ECOG). A combination of mitoxantrone, etoposide (VP-16), and high-dose cytarabine (ARA-C) were administered over a five day period. Thirty-four patients were eligible for follow-up subsequent to treatment. Twenty-seven patients were in first relapse and seven were in second relapse. Fifteen of the thirty-four patients treated were given two cycles of induction chemotherapy. The complete remission (CR) rate for the entire group treated was 17%. The median duration of the CR was 2.4 months and the estimated median survival for first relapse patients was 4.5 months and 5.0 months for second relapse patient group. There were five deaths attributable to toxicity associated with the chemotherapy. The study emphasizes the difficulty in achieving durable remissions in adult patients with relapsed ALL.     

Intensive short term therapy with granulocyte-macrophage-colony stimulating factor support, similar to therapy for acute myeloblastic leukemia, does not improve overall results for adults with acute lymphoblastic leukemia. GOELAMS Group.

BACKGROUND: Despite modern treatment programs, less than 20% of adult cases of acute lymphoblastic leukemia (ALL) are cured. For relapsing and/or refractory patients, use of high dose cytosine arabinoside (ara-C) and anthracyclin achieved a complete remission (CR) rate of up to a 75%. The aim of this study was to evaluate in adult patients with ALL 1) the CR rate of a chemotherapy schedule similar to a schedule for acute myeloblastic leukemia (AML) patients, 2) the antileukemic value and the tolerance of 3 intensive stage treatments, and 3) the impact of recombinant granulocyte-macrophage-colony stimulating factor (rGM-CSF) on chemotherapy-induced neutropenia and infectious complications, as well as the effect of dose intensity. METHODS: Between November 1990 and April 1992, 67 patients ages 15-55 years with de novo ALL were randomly assigned to receive either rGM-CSF or placebo. The induction treatment consisted of idarubicin, methylprednisolone, and high dose ara-C. After achieving CR, patients up to age 45 years who had an HLA-identical sibling were assigned to undergo allogeneic bone marrow transplantation (BMT). All remaining patients received a first course of early intensification with high dose ara-C, mitoxantrone, etoposide, and methylprednisolone, followed by autologous, unpurged BMT. RESULTS: Of the 64 eligible patients, 50 (78%) achieved CR. Sixteen allogeneic and 18 autologous BMTs were performed. The median survival was 10.2 months. The 4-year survival was 24%. rGM-CSF only improved the incidence of severe mucositis during the induction course (P = 0.003) and probably also improved the median duration of fever (P = 0.07). CONCLUSIONS: This schedule, similar to that for the treatment of AML patients, with early BMT included, did not prove to be a satisfactory approach to the treatment of most adult ALL patients, although CR was achieved in 78% of cases. In this study, no major improvement was obtained with rGM-CSF therapy.     

Primary refractory and relapsed adult acute lymphoblastic leukemia: characteristics, treatment results, and prognosis with salvage therapy.

BACKGROUND: Relapses continue to be problematic for adults with acute lymphoblastic leukemia (ALL). New therapies generally are first tested in the salvage setting prior to incorporation into frontline regimens. Defining the prognosis at relapse (or at failure of induction) and subsequently predicting outcome would be useful to select the population in whom to test new strategies, rather than attempting traditional reinduction therapy. METHODS: Between March 1980 and March 1997, 314 eligible adults with primary refractory (24%) or primary relapsed (76%) ALL were treated with various chemotherapy or stem cell transplantation (SCT) regimens. The Cox proportional hazards model was used to assess biologic factors and disease history in relation to survival. RESULTS: A complete remission (CR) was achieved in 97 patients (31%), 21% died prior to a response, and 49% were refractory to salvage therapy. Of the 76 patients refractory to induction therapy for their de novo ALL, 26 patients (34%) achieved a CR with salvage therapy. The median overall CR duration was 6 months. The median overall survival was 5 months; 24% of the patients were alive at 1 year, and the projected survival at 5 years was 3%. Nineteen patients were alive at the time of last follow-up, 10 with 6 weeks to 10 years of continuous CR from the time of their first salvage therapy. SCT consolidation in second CR was performed in 25% of patients; 28% of those who received allogeneic SCT remain in continuous CR at 4 months, 2(1/2) years, 3(1/2) years, and 10 years, whereas all 8 who received autologous SCT have relapsed. Favorable factors for longer survival by multivariate analysis were age <40 years, absence of circulating blasts, and first CR duration longer than 1 year. Patients were stratified into 4 risk groups: Group 1, with no unfavorable features or only short initial CR duration; Group 2, with only increased age or peripheral blasts; Group 3, with any 2 unfavorable features; and Group 4, with all 3 unfavorable features. The median survival times for each group were 11, 6, 4, and 2 months, respectively; 1-year survival rates were 44%, 25%, 12%, and 9%, respectively (P < 0.01). The resulting model was also predictive for CR rates; the corresponding CR rates were 47%, 35%, 14%, and 9%, respectively (P < 0.01). CONCLUSIONS: Salvage therapy for adult ALL patients continues to yield poor results, but it is an area of research where it may be possible to discover new agents or strategies to be incorporated into frontline therapy. The prognostic model derived will be utilized prospectively to select patients for new therapeutic strategies involving such novel agents as liposomal compounds, purine nucleoside phosphorylase inhibitors, and monoclonal antibodies.     

Outcome of treatment after first relapse in adults with acute lymphoblastic leukemia initially treated by the LALA-94 trial.

Fifty-four percent of adults with acute lymphoblastic leukemia (ALL) who entered the LALA-94 trial experienced a first relapse. We examined the outcome of these 421 adult patients. One hundred and eighty-seven patients (44%) achieved a second complete remission (CR). The median disease-free survival (DFS) was 5.2 months with a 5-year DFS at 12%. Factors predicting a better outcome after relapse were any transplant performed in second CR (P<0.0001), a first CR duration >1 year (P=0.04) and platelet level >100 x 10(9)/l at relapse (P=0.04). Risk groups defined at diagnosis and treatment received in first CR did not influence the outcome after relapse. The best results were obtained in a subset of patients who were eligible for allogeneic stem cell transplantation (SCT). Geno-identical allogeneic SCT was performed in 55 patients, and 3 patients received donor lymphocyte infusions. Forty-four transplantations were performed from an unrelated donor (of which four were cord blood). We conclude that most adult patients with recurring ALL could not be rescued using current available therapies, although allogeneic SCT remains the best therapeutic option.     

Short-term chemotherapy of poor-prognosis metastatic breast cancer with three non-cross resistant chemotherapy regimens. A Southwest Oncology Group Study

A Southwest Oncology Group pilot study was designed to evaluate a brief, 4.5-month induction course of chemotherapy with three presumably non-cross resistant regimens in poor-prognosis metastatic breast cancer. Sixty-three patients were treated with doxorubicin, cyclophosphamide, plus vincristine on day 1, methotrexate followed 30 minutes later by 5-fluorouracil (5-FU) on day 22, and mitomycin C plus 3 days of vinblastine on day 43. All three sequential regimens were repeated once and therapy was then discontinued in responding patients. The same chemotherapy was reinstituted at the time of relapse. The overall response rate to the induction chemotherapy was 35% and included only one complete response (2%). Median response duration was 9 months. Respondents were off all therapy for a median of 5 months (range, 1-12+ months) and were followed without evidence of progressive disease. Response to retreatment was 30% with no complete responses seen. Overall median survival from the data of diagnosis of metastatic disease was 24 months, with a median survival of 14 months from the date of initiation of therapy. Toxicity for this induction regimen was moderate with two treatment-related deaths secondary to myelosuppression. While the results of this pilot study fail to support the use of non-cross resistant regimens in breast cancer, short-term therapy appears to have no adverse effect on survival and resulted in significant periods during which no therapy was given, resulting in a reduction in overall toxicity.     

Cytosine arabinoside/cyclophosphamide pulses during continuation therapy for childhood acute lymphoblastic leukemia. Potential selective effect in T-cell leukemia

One hundred seventy-seven children with acute lymphoblastic leukemia (ALL) were admitted to a study designed to determine whether pulses of cytosine arabinoside (ara-C) and cyclophosphamide (cyclo) would improve disease-free survival (DFS). All patients received vincristine, prednisone, and asparaginase for remission induction, CNS prophylaxis with cranial irradiation and intrathecal methotrexate, and continuation therapy with 6-mercaptopurine plus methotrexate. Forty-seven of 101 patients with non-T ALL and 18 of 26 patients with T-cell ALL received ara-C/cyclo pulses every eight weeks during continuation therapy. The age, sex, and initial white cell count distributions were similar in both treatment groups. Patients with non-T-cell ALL had similar DFS with or without ara-C/cyclo pulses (36% versus 48%; P = 0.32). Ara-C/cyclo pulses significantly improved DFS in children with T-cell ALL (36% versus 0%; P = 0.015). Toxicities of the ara-C/cyclo pulses included reversible pancytopenia, drug induced fever, fever associated with neutropenia, and death in one patient from systemic candidiasis while neutropenic. This is the first clinical evidence to indicate that the combination of ara-C/cyclo used during continuation therapy is selectively beneficial in T-cell ALL.     

Therapy with imatinib mesylate (Glivec) preceding allogeneic stem cell transplantation (SCT) in relapsed or refractory Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL).

Imatinib has pronounced antileukemic activity in Ph+ALL, although responses are usually short. To determine whether imatinib may facilitate allogeneic SCT in relapsed or refractory Ph+ALL, we evaluated 46 consecutive, not previously transplanted patients who were enrolled in phase II studies of imatinib. Of 30 patients eligible for SCT, 22 (73%) were actually transplanted. Ten patients were in complete hematologic remission (CHR) (n = 5) or had a complete marrow response (CMR) (n = 5) at the time of SCT, 12 patients had again relapsed or were refractory. After SCT, 18 patients were in complete remission, one patient was refractory, three patients died prior to response assessment. Seven patients (32%) are in ongoing complete remission with a median follow-up of 9.4 (range 1.7-23.8) months. Seven patients (32%) relapsed a median of 5.2 months after SCT. Transplant-related mortality (TRM) was 36%. Probability of disease-free survival (DFS) is 25.5 +/- 9.8% overall and 51.4 +/- 17.7% when SCT was performed in CHR or CMR, compared with 8.3 +/- 8% for SCT during overt leukemia (P = 0.06). In conclusion, imatinib is a well-tolerated salvage therapy prior to allogeneic SCT in patients with Ph+ALL, but requires that SCT be performed within a few weeks of starting treatment to avoid resistance. Disease status at time of transplantation is an important determinant of DFS and TRM.