melphalan and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Female; Graft vs Host Reaction; HLA Antigens; Humans; Infant; Male; Melphalan; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation, Autologous; Transplantation, Homologous

The usage of a T-cell depleted, reduced intensity conditioning (RIC) approach to haematopoietic cell transplantation (HCT) in adult patients with acute lymphoblastic leukaemia (ALL) over 40 years of age and in first complete remission (CR) has resulted in encouraging rates of event-free and overall survival in a population of adults with high risk disease. However, relapse rates remain high-with disease progression being the major cause of treatment failure. Using different, more powerful conditioning approaches is the logical next step in examining the role of RIC allogeneic HCT in adult ALL.. The ALL-RIC trial is a two-arm, phase II, multicentre, randomised clinical trial in adult patients with ALL in first or second CR, who are undergoing allogeneic HCT. Comparison of a novel RIC transplant conditioning regimen using reduced-dose total body irradiation (TBI), cyclophosphamide and alemtuzumab, is made against a standardised RIC approach using fludarabine, melphalan and alemtuzumab. The primary outcome of the study is disease-free survival at 3 years, defined as time from randomisation to the first of either relapse or death from any cause. Patients who are still alive and progression-free at the end of the trial will be censored at their last date known to be alive. Secondary outcomes include overall survival and non-relapse mortality.. The protocol was approved by the East Midlands-Leicester Central Research Ethics committee (18/EM/0112). Initial approval was received on 12 June 2018. Current protocol version (V.6.0) approval obtained on 18 November 2019. The Medicines and Healthcare products Regulatory Agency (MHRA) also approved all protocol versions. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications.. EudraCT Number: 2017-004800-23.ISRCTN99927695.

Topics: Acute Disease; Adult; Alemtuzumab; Clinical Trials, Phase II as Topic; Cyclophosphamide; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Multicenter Studies as Topic; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Randomized Controlled Trials as Topic; Whole-Body Irradiation

Approximately 5% to 20% of patients who undergo total body irradiation (TBI) in preparation for hematopoietic cell transplantation (HCT) can develop extramedullary (EM) relapse. Whereas total marrow and lymphoid irradiation (TMLI) provides a more conformally targeted radiation therapy for patients, organ sparing has the potential to place the patient at a higher risk for EM relapse than TBI. This study evaluated EM relapse in patients treated with TMLI at our institution.. Patients eligible for analysis had been enrolled in 1 of 3 prospective TMLI trials between 2006 and 2012. The TMLI targeted bones, major lymph node chains, liver, spleen, testes, and brain, using image-guided tomotherapy with total dose ranging from 12 to 15 Gy.. A total of 101 patients with a median age of 47 years were studied. The median follow-up was 12.8 months. Incidence of EM relapse and bone marrow (BM) relapse were 12.9% and 25.7%, respectively. Of the 13 patients who had EM relapse, 4 also had BM relapse, and 7 had EM disease prior to HCT. There were a total of 19 EM relapse sites as the site of initial recurrence: 11 soft tissue, 6 lymph node, 2 skin. Nine of these sites were within the target region and received ≥12 Gy. Ten initial EM relapse sites were outside of the target region: 5 sites received 10.1 to 11.4 Gy while 5 sites received <10 Gy. Pretransplantation EM was the only significant predictor of subsequent EM relapse. The cumulative incidence of EM relapse was 4% at 1 year and 11.4% at 2 years.. EM relapse incidence was as frequent in regions receiving ≥10 Gy as those receiving <10 Gy. EM relapse rates following TMLI that included HCT regimens were comparable to published results with regimens including TBI and suggest that TMLI is not associated with an increased EM relapse risk.

Topics: Adolescent; Adult; Age Factors; Aged; Antineoplastic Agents; Blast Crisis; Bone Marrow; Busulfan; Child; Cyclophosphamide; Etoposide; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Lymphatic Irradiation; Melphalan; Middle Aged; Myelodysplastic Syndromes; Organ Sparing Treatments; Organs at Risk; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Radiotherapy Dosage; Recurrence; Transplantation Conditioning; Vidarabine; Whole-Body Irradiation; Young Adult

We investigated the administration of i.v. BU combined with melphalan (Mel) in patients with ALL undergoing allogeneic hematopoietic SCT. Forty-seven patients with a median age of 33 years (range 20-61) received a matched sibling (n=27) or matched unrelated donor transplant (n=20) for ALL in first CR (n=26), second CR (n=13), or with more advanced disease (n=8). BU was infused daily for 4 days, either at a fixed dose of 130 mg/m² (5 patients) or using pharmacokinetic (PK) dose adjustment (42 patients), to target an average daily area-under-the-curve (AUC) of 5000 μmol/min, determined by a test dose of i.v. BU at 32 mg/m². This was followed by a rest day, then two daily doses of Mel at 70 mg/m². Stem cells were infused on the following day. The 2-year OS, PFS and non-relapse mortality (NRM) rates were 35% (95% confidence interval (CI), 23-51%), 31% (95% CI, 21-48%) and 37% (95% CI, 23-50%), respectively. Acute NRM at 100 days was favorable at 12% (95% CI, 5-24%); however, the 2-year NRM was significantly higher for patients older than 40 years, 58% vs 20%, mainly due to GVHD.

Topics: Adult; Age Factors; Antineoplastic Agents, Alkylating; Busulfan; Drug Therapy, Combination; Female; Follow-Up Studies; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Incidence; Infusions, Intravenous; Male; Melphalan; Middle Aged; Myeloablative Agonists; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Secondary Prevention; Survival Analysis; Texas; Transplantation Conditioning; Transplantation, Homologous; Young Adult

The aim of this prospective study was to investigate the feasibility of reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (SCT) in 37 adults with high-risk acute lymphoblastic leukemia (ALL) in first (n=30) or second (n=7) complete remission (CR). All patients were treated with fludarabine (150 mg/m(2)) and melphalan (140 mg/m(2)) followed by transplantation from matched sibling (n=27) or unrelated (n=10) donors. The indications for reduced-intensity conditioning allogeneic SCT (RIC-SCT) were as follows: (1) > or = 50 years, 16 (43.2%) and (2) decreased organ function or active infections, 21 (56.8%). Graft-versus-host disease (GVHD) prophylaxis consisted of calcineurin inhibitor (cyclosporine for sibling and tacrolimus for unrelated transplants) and methotrexate. The cumulative incidence of acute (grades II-IV) and chronic GVHD was 43.2 and 65.6%, respectively. After a median follow-up of 36 months for surviving transplants, the 3-year relapse, non-relapse mortality, disease-free survival and overall survival rates were 19.7, 17.7, 62.6 and 64.1%, respectively. Transplants in first CR showed better transplantation outcomes than those in second CR. The potential of antileukemic activity of chronic GVHD was also found. This study suggests that RIC-SCT is a potential therapeutic approach for adults with high-risk ALL in remission who are ineligible for myeloablative transplantation.

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Feasibility Studies; Female; Graft Survival; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Remission Induction; Risk Factors; Survival Rate; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine; Young Adult

Results of allogeneic hematopoietic stem cell transplantation (HCT) to treat advanced leukemia or myelodysplastic syndrome (MDS) remain poor due to excessive relapse and transplant-related mortality. To improve transplant outcome in this patient population, 43 patients (median age, 46.1 years) with high-risk or advanced lymphoid (n = 5) or myeloid malignancy (n = 38) were prospectively enrolled on a pilot trial of cytoreduction with intravenous busulfan and melphalan followed by an unmodified HLA-A, -B, and -DRbeta1-matched related (n = 18) or unrelated (n = 25) HCT. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. Thirty-four patients had > or = 5% blasts at the time of HCT; 12 of these had > 20% blasts. Seventeen patients had unfavorable cytogenetics, 8 patients underwent transplantation for secondary MDS or acute myelogenous leukemia, and 4 patients had relapsed after a previous allogeneic transplantation. Although mucositis was the most significant regimen-related toxicity, requiring the addition of folinic acid rescue and failure to receive all 4 doses of methotrexate in 23 patients, the nonrelapse mortality at 30 and 100 days was low at 0% and 16%, respectively. The cumulative incidence of grade II-IV acute GVHD was 24%, and that of extensive chronic GVHD was 7%. With a minimum follow-up of 18 months, the estimated 3-year overall survival is 37% and the estimated disease-free survival (DFS) is 33%. For 18 patients with MDS (< or = RAEB-2) or high-risk myeloproliferative disorder, the estimated 3 year DFS is 61%. These data demonstrate the curative potential of this regimen in patients with high-risk myeloid malignancies.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Child, Preschool; Female; Hematopoietic Stem Cell Transplantation; Histocompatibility Testing; Humans; Immunosuppressive Agents; Infant; Leukemia, Myeloid, Acute; Male; Melphalan; Methotrexate; Middle Aged; Myelodysplastic Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Survival Analysis; Tacrolimus; Transplantation Conditioning

A total of 65 adults with acute lymphoblastic leukemia (ALL) received 200 mg/m2 melphalan and an autograft in first remission, with a plan to receive 6-mercaptopurine (6MP), methotrexate (MTX), and vincristine-prednisone (VP) for 2 years afterwards. There was no transplant-related mortality. In all, 69% of patients received 6MP, 54% received MTX, and 49% received VP. The cumulative incidence of relapse at 5 years was 52%. The 5-year probabilities of disease-free (DFS) and overall (OS) survival were 48 and 55%. Age >30 years, >4 weeks to attain remission, and t(9;22) or t(4;11) karyotypes were adverse prognostic features. Patients with 0 (standard risk), 1 (intermediate risk), and 2-3 (high risk) adverse features had 5-year cumulative incidences of relapse of 19, 59, and 100% (P<0.0001), and 5-year probabilities of DFS of 80, 41, and 0% (P<0.0001). The 5-year probabilities of DFS for patients receiving 0, 1, 2, and 3 maintenance therapy agents were 19, 40, 51, and 70% (P=0.0097). Maintenance therapy intensity was an independent determinant of outcome in Cox analysis. These data show that a high-dose melphalan-based autograft is safe and could be widely applicable in ALL in first remission, and that maintenance chemotherapy very likely contributes to improved outcome of autografted ALL patients.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Female; Humans; Male; Melphalan; Middle Aged; Peripheral Blood Stem Cell Transplantation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proportional Hazards Models; Recurrence; Remission Induction; Survival Analysis; Transplantation, Autologous

Between September 1986 and June 1997, 24 children with high-risk ALL in CR1 were allografted after TAM (fractionated TBI, high-dose Ara-C, and melphalan; n = 10) or BAM protocol (busulfan, high-dose Ara-C, and melphalan; n = 14). The EFS for transplants from sibling donors was 33% with TAM and 62% with BAM (P = 0.148). The probability of acute GvHD was 70% with TAM and 15% with BAM (P = 0.003). Four of 17 evaluable patients relapsed: one after TAM and three after BAM. In all, 46 other children transplanted in CR beyond CR1 were studied for sequelae. Long-term side effects were more frequent in TAM vs BAM. In children with ALL, busulfan may be a good alternative to TBI to improve the quality of life.

Topics: Adolescent; Bone Marrow Transplantation; Busulfan; Child; Child, Preschool; Cytarabine; Female; Graft vs Host Disease; Humans; Immunophenotyping; Karyotyping; Male; Melphalan; Organophosphates; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Time Factors; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome

Although definite risk classes are well known, risk-adapted modulation of first-line therapy is seldom attempted in adult ALL. So, a prospective validation of the therapeutic efficacy of a protocol (or a component thereof) in specific risk groups is uncommon.. From 1996-1999 a risk-oriented program (08/96) was evaluated in 102/121 unselected patients (median age 35 years, blast count 0-450 x 10(9)/l, 100 B(lin) (lineage), 21 T(lin)) responsive to induction therapy. The standard risk (SR) class was B(lin) CD10+ Ph- with blasts < 10 x 10(9)/l (prior studies: disease-free survival (DFS) rate 52% at five years with dose-intensive anthracycline-containing programs). The SR protocol was therefore anthracycline-rich (early consolidation cycles with total idarubicin 96 mg/m2), and comprised long-term maintenance. High-risk (HR) patients were eligible to the following three options: allogeneic hematopoietic stem cell transplantation (HSCT) from related family donor; short sequence with high-dose cyclophosphamide-cytarabine-methotrexate followed by melphalan/total body irradiation with autologous HSCT; or T(lin) ALL chemotherapy regimen inclusive of high-dose cytarabine and methotrexate.. Treatment realization and three-year DFS rates according to risk class, HR subset and postremission treatment intensity were the following. SR group (n = 28): realization rate 93%, DFS 68.5%. HR group (n = 74): realization rate 80%, DFS 39% (P = 0.052 vs SR category). In HR group, three-year DFS rates by disease subtype were the following. B(lin) Ph- (n = 35) 43%; Ph+ (n = 19) 13% at 2.7 years (P = 0.006 vs other HR subtypes); T(lin) (n = 18) 59.5%. And DFS rates by treatment intensity were: allograft (n = 21) 40%; autograft (n = 28) 27%; shift to SR protocol (n = 13) 52% (P = ns vs allograft/autograft); T(lin) program (n = 10) 57%. Matched analyses of treatment protocols and disease subtypes suggested a possible therapeutic role of the autograft regimen in B(lin) Ph- ALL with a blast count < 25 x 10(9)/l, and of T(lin) protocol for T(lin) ALL. Comparisons with retrospective control cohorts were confirmatory of anthracycline activity in SR subclass.. The intended strategy was applicable to the majority of study patients, confirming the value of anthracyclines in SR class and, preliminarily, the usefulness a T(lin)-specific treatment. Apart from the case of Ph+ ALL, the indications for high-dose procedures with HSCT remains largely undetermined in this study.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytarabine; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Idarubicin; Male; Melphalan; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk Factors; Transplantation, Homologous; Whole-Body Irradiation

From 1984 to 1996, 31 consecutive children without sibling donors, aged 5-19 years (median 8) with acute lymphoblastic leukaemia (ALL) in second complete remission (CR), received unpurged autologous bone marrow transplantation (ABMT) after melphalan and single fraction total body irradiation (TBI). ABMT was performed using fresh unmanipulated marrow harvested after standard reinduction and consolidation therapy 2-11 months (median 5) after relapse. With a median survival of 2.9 years the probability of survival for all patients in continuing second CR was 45.1% (95% CI, 24%-62%) after 5 years. Regimen-related and non-leukaemia mortality was 7% (95% CI, 2%-26%). The longest time to second relapse from ABMT was 3.1 years. Pituitary and gonadal dysfunction requiring hormonal replacement therapy occurred in the majority of long-term survivors. Twelve patients developed cataracts. ABMT with melphalan/single fraction TBI has proved an effective anti-leukaemia treatment with low regimen-related mortality but significant long-term morbidity. The current approach of allogeneic BMT from an unrelated donor when no sibling donor is available, following conditioning with cyclophosphamide/ fractionated TBI has resulted in a reduced relapse rate and improved short-term overall survival in the treatment of relapsed childhood ALL. However, long-term results are awaited.

Topics: Adolescent; Bone Marrow Transplantation; Cataract; Child; Child, Preschool; Disease-Free Survival; Female; Fever; Follow-Up Studies; Gonadal Disorders; Graft Survival; Human Growth Hormone; Humans; Infant; Male; Melphalan; Mouth Mucosa; Neutrophils; Platelet Count; Pneumocystis Infections; Pneumonia, Pneumocystis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Sepsis; Stomatitis; Survival Rate; Thyroxine; Time Factors; Transplantation Conditioning; Transplantation, Autologous; Whole-Body Irradiation

Aiming to target the minimal residual disease in patients with multiple myeloma, a phase I/II single centre study was undertaken for feasibility and tolerance of intensive acute lymphoblastic leukaemia consolidation chemotherapy (ALL-IC) as part of a strategy for post-transplant consolidation targeted at pre-B cells. Seventeen newly diagnosed patients with myeloma (median age 55 years; 30-65) were initially treated with courses of infused cyclophosphamide, vincristine, adriamycin and methylprednisolone (C-VAMP) followed by melphalan 200 mg/m2(HDM) and peripheral blood stem cell rescue (PBSC). Forty-seven percent were in CR and the rest in PR after HDM. ALL-IC consisted of vincristine, daunorubicin, etoposide, cytarabine, 6-thioguanine and prednisolone given over 5 days. All patients became neutropenic (<0.5 x 109/l) at a median of 10 days (4-18) and one of the 17 patients (5.8%) died 15 days post ALL-IC of sepsis. A further four have died of relapse with an overall survival (OS) of 67% at 4 years. Two of nine patients in PR at the time of ALL-IC achieved CR. Matched-pair analysis of 34 control patients shows no difference for OS and event-free survival between ALL-IC and controls. We conclude that ALL-IC given to myeloma patients after HDM/PBSC is as safe as when used in ALL and warrants further assessment in randomised trials for myeloma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation, Autologous; Treatment Outcome

Patients with acute leukemias relapsing within 1 year of an allogeneic BMT have a poor prognosis. We studied the use of melphalan 180 mg/m2 followed by allogeneic peripheral blood stem cells (PBSC) as salvage treatment for patients relapsing after related (n = 7) or matched unrelated transplants (n = 3). Diagnoses were AML (n = 4), ALL (n = 3), biphenotypic acute leukemia (n = 2) and CML in blast crisis (n = 1). Eight patients were beyond first relapse and none were in remission. The median time from previous transplant to relapse was 146 days (range 66-206). The melphalan dose was 90 mg/m2 intravenously on days -4 and -3 with PBSC infusion on day 0. GVHD prophylaxis consisted of cyclosporine and methylprednisolone. The median time to an absolute neutrophil count >0.5 x 10(9)/l and to a platelet count >20 x 10(9)/l was 11 and 13 days, respectively. All engrafting patients (n = 8) had 100% donor cells. Two patients died before day 30, but no other grade 3 or 4 toxicity occurred. Acute GVHD grades II-III occurred in two subjects, and chronic GVHD in four. Seven patients achieved CR, but relapsed at a median of 116 days (range 56-614). Leukemia was the cause of death in eight patients. Median survival was 149 days (range 6-614). This treatment produced responses in the majority of this poor prognosis group. However, durable remissions were not observed, and new treatments to consolidate the responses achieved in this setting are needed. This regimen could be considered for short-term disease control to facilitate donor lymphocyte infusion-based immunotherapy or other measures to prevent disease recurrence.

Topics: Acute Disease; Adult; Antineoplastic Agents, Alkylating; Bone Marrow Transplantation; Child; Chronic Disease; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Pilot Projects; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Transplantation Chimera

We investigated the use of a new conditioning regimen followed by allogeneic bone marrow transplantation (BMT) for treating children with acute lymphoblastic leukaemia (ALL) after relapse within 6 months of the completion of therapy. One hundred and sixteen children with acute lymphoblastic leukaemia in second or subsequent complete remission (CR) underwent allogeneic bone marrow transplantation from HLA-identical siblings after a preparative regimen comprising total body irradiation (TBI), high-dose cytosine arabinoside and melphalan (TAM regimen). The Kaplan-Meier product-limit estimate (mean +/- SE) of disease-free survival (DFS) at 7 years was 59.5 +/- 9% (95% confidence interval). The estimated chance of relapse was 22.5 +/- 15% with a median follow-up of 88.5 months (range 51-132). 26 patients (22.4%) died with no evidence of recurrent leukaemia, mainly from interstitial pneumonitis, veno-occlusive disease or acute graft-versus-host disease (GVHD). Three factors significantly affected DFS: acute GVHD. site of relapse and, for children in second remission after a marrow relapse, the disease status at the time of transplantation. The DFS were 59.02 +/- 12.6%, 37.5 +/- 19.8% and 774 +/- 15% among patients in CR2 after a marrow relapse, in CR3 or in untreated partial marrow relapse, and in CR2 after an isolated CNS relapse, respectively. The lowest DFS was seen in children with acute GVHD grades 3-4. Two significant factors were associated with relapse: the marrow status at the time of transplantation and chronic GVHD. The relapse rate was lower among children in CR2 or with chronic GVHD. We conclude that transplantation after the TAM regimen is an effective therapy for this population with acceptable toxicity, particularly for children in second remission after a very early marrow relapse, or those with early isolated CNS involvement.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Central Nervous System Neoplasms; Child; Child, Preschool; Cytarabine; Disease-Free Survival; Female; Graft vs Host Disease; Humans; Male; Melphalan; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Recurrence; Testicular Neoplasms; Transplantation, Homologous; Whole-Body Irradiation

During 1984-86, 23 patients (5-37 years, median 16) with acute lymphoblastic leukemia (ALL) in first remission (n = 11) or beyond (n = 12) underwent autologous transplantation (ABMT) using marrow purged with the rat anti-CD52 monoclonal antibody Campath-1M after melphalan and total-body irradiation (TBI). Median time to 0.5 x 10(9)/L neutrophils and 50 x 10(9)/L platelets was 38 and 51 days respectively. Myeloid engraftment was significantly slower compared with ALL patients receiving unpurged marrow (P = .01). Eight patients died due to transplant-related causes 53-205 days after the procedure. Six of eight patients receiving 1150 cGy TBI died of toxicity compared with two of 15 receiving less than 1150 cGy (P = .006, Fisher's exact test). Nine patients relapsed at 45-195 days (median 97); eight died and one is alive at nine years in a chemotherapy-induced remission. Six patients are alive and well in continuous remission 9-10 years (median 10) after transplant. The 10-year probabilities of disease-free survival and relapse are 26% (95% CI: 11-45%) and 51% (95% CI: 37-59%) respectively. We conclude that it is feasible to purge marrow for autografting using Campath-1M without killing normal stem cells. Myeloid engraftment is slow but consistent, and long-term survival is seen in a proportion of patients. The role of CD52 monoclonal antibodies for purging in ALL still requires further study.

Topics: Adolescent; Adult; Animals; Antibodies, Monoclonal; Antigens, CD; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Bone Marrow Transplantation; CD52 Antigen; Child; Child, Preschool; Combined Modality Therapy; Female; Follow-Up Studies; Glycoproteins; Humans; Male; Melphalan; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Rats; Time Factors; Transplantation, Autologous; Whole-Body Irradiation

Attempts to improve the efficacy of pretransplant conditioning regimens have been published, the potential of a better antileukemic effect being impaired by more frequent and severe toxicities. The efficacy of an intensified regimen, TAM (TBI, high-dose cytosine arabinoside and melphalan), is evaluated by analyzing long-term follow-up of a homogenous group of 42 high-risk ALL patients allografted in first CR. Age at time of BMT was 25.9 +/- 10.4 years (3-41). Twenty-two patients had more than three adverse prognostic factors. Ten patients had a Ph chromosome. Probability of overall survival was 45 +/- 9%, and for all surviving patients median follow-up time was 66 months. Event-free survival was 40 +/- 8% at 7 years after transplantation and the expected relapse rate reached 31%. Twenty-two deaths occurred, six after a relapse but 16 appeared to be directly due to the BMT procedure. None of the pretransplant characteristics significantly affected outcome after BMT. TAM appeared to be an efficient antileukemic therapy for conditioning high-risk ALL patients before allogeneic transplantation, but was still very toxic. The use of TAM in adult ALL patients in first CR is not recommended and the real role of intensified conditioning regimens remains to be demonstrated.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Burkitt Lymphoma; Child; Child, Preschool; Combined Modality Therapy; Cytarabine; Female; Follow-Up Studies; Humans; Leukemia-Lymphoma, Adult T-Cell; Male; Melphalan; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Whole-Body Irradiation

Of 41 pediatric patients currently alive after total body irradiation (TBI) and bone marrow transplantation (BMT), 30 (allogeneic 20, autologous 10) participated in the study. Pre-transplant therapy included high-dose cyclophosphamide (CY) and TBI (n = 12), high-dose CY alone (n = 4), high-dose Ara C and TBI (n = 5), cisplatinum, high-dose melphalan, VP-16 and TBI (n = 9). Acute cardiotoxicity was suggested by a > 15% decrease in the QRS voltage sum of the limb leads in all patients. Late cardiotoxicity was evaluated 0.5-10 years (median 5 years) post-transplant by ECG, chest radiograph, radionuclide cineangiography (RNCA) and echocardiography (ECHO). Six patients had a persistent decrease in the QRS amplitudes. They were all asymptomatic but had abnormal systolic function at the time of the study. BMT patients differed from their controls in the mean values of both the systolic and diastolic indices of myocardial function shown by RNCA and ECHO. Treatment was associated with decreased myocardial contractility. Isovolumic relaxation time and deceleration time were longer in BMT patients than in controls. Myocardial damage seemed to be worst after CY while high-dose Ara C was tolerated best. We conclude that both acute and late cardiotoxicity may occur after BMT, calling for long-term cardiac follow-up.

Topics: Adolescent; Adult; Blood Pressure; Bone Marrow Transplantation; Child; Child, Preschool; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Dose-Response Relationship, Drug; Echocardiography; Female; Heart; Humans; Infant; Leukemia, Myeloid, Acute; Male; Melphalan; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Radionuclide Angiography; Time Factors; Transplantation, Autologous; Transplantation, Homologous; Whole-Body Irradiation

In a randomised multicentre trial a combination of methylprednisolone, vincristine, lomustine, cyclophosphamide and melphalan (MOCCA) was compared with the same regimen omitting methylprednisolone after the first course (COLA) in previously untreated patients with multiple myeloma. The MOCCA arm showed a response rate of 72% among 79 patients and the COLA arm a response rate of 60% among 59 patients. This difference was not statistically significant. The median survival time was 56 months in the MOCCA arm and 61 months in the COLA arm. There was a slight increase of early deaths (within the first 6 months) in the MOCCA arm as compared with the COLA arm. We conclude that, in multidrug therapies, the continuation of corticosteroid at conventional dosage beyond the first course does not improve response rate or survival time in multiple myeloma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Female; Humans; Leukemia, Myeloid, Acute; Lomustine; Male; Melphalan; Methylprednisolone; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Survival Rate; Vincristine

Topics: Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Cyclophosphamide; Cytarabine; Graft vs Host Disease; Humans; Melphalan; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Whole-Body Irradiation

Sixteen patients with poor-prognosis acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and non-Hodgkin's lymphoma (NHL) underwent conditioning with busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) (BUCY-2) plus melphalan (90 or 135 mg/m2) and autologous bone marrow transplantation (AuBMT) in a phase I study. At the melphalan dose of 90 mg/m2, grade greater than or equal to 3 regimen-related toxicity (RRT) was observed in five patients (31%; 95% confidence interval [CI], 11% to 59%), with hepatic (venoocclusive disease [VOD]) and urinary (hemorrhagic cystitis) RRT being the most frequent complications. Further escalation of the melphalan dose to 135 mg/m2 was deemed excessively toxic, as three of five patients had grade greater than or equal to 3 RRT. Following this experience, 21 patients with multiple myeloma (MM) and chronic myelogenous leukemia (CML) were treated with BUCY-2 plus melphalan 90 mg/m2 and AuBMT in separate studies. Three of these patients--all with extensively pretreated MM--had grade greater than or equal to 3 RRT (14%; 95% CI, 3% to 36%); no others had grade greater than or equal to 3 RRT. Therefore, a total of eight of the 37 patients (22%; 95% CI, 10% to 38%) who received BUCY-2 plus melphalan 90 mg/m2 conditioning developed grade greater than or equal to 3 RRT; three of these patients (8%; 95% CI, 3% to 25%) died of RRT. Although limited by the relatively small number of patients, our analysis of the patients receiving this regimen showed that the presence of parameters denoting the lymphoid diagnostic group (ie, ALL, NHL, and MM), more extensive pretreatment, and/or more advanced disease status were associated with a higher incidence of grade greater than or equal to 3 RRT. Response data on the AML, ALL, and NHL patients who received BUCY-2 plus melphalan 90 mg/m2 were analyzed: three patients (all with AML in first or second remission) are leukemia-free at 3.0, 2.8, and 1.4 years after AuBMT. The actuarial 2-year event-free survival in this group is 17% (95% CI, 5% to 54%). Response data on the MM and CML patients will be reported subsequently. BUCY-2 plus melphalan at a dose of 90 mg/m2 before AuBMT produces acceptable toxicity in patients who are not heavily pretreated. A full evaluation of the antineoplastic effects of this regimen requires further study.

Topics: Actuarial Analysis; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Busulfan; Combined Modality Therapy; Cyclophosphamide; Drug Evaluation; Female; Humans; Leukemia; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Survival Analysis; Transplantation, Autologous

We report the safety and efficacy of 34 consecutive autologous bone marrow transplant (ABMT) procedures performed in adult patients with high-grade lymphoid malignancy after remission induction therapy. Fifteen patients with acute lymphoblastic leukemia (ALL) and six with high-grade non-Hodgkin's lymphoma (NHL) received pretransplant conditioning with intravenous (IV) melphalan and fractionated total body irradiation (TBI). Thirteen other patients with NHL were conditioned with melphalan alone, having previously received local involved field radiotherapy. Unmanipulated noncryopreserved autologous marrow was reinfused within 48 hours of harvesting. Engraftment occurred in all patients with medians of 10 days of neutropenia (neutrophils less than 0.5 x 10(9)/L), 4-day platelet transfusion requirement, 3 U packed RBC transfusion, and 18 days in hospital posttransplant. There were no procedure-related deaths. Actuarial disease-free survival in the 13 patients with ALL receiving autotransplant early in first remission is 48% with a median follow-up of 3 years. Two other ALL patients who had autotransplants after a period of maintenance therapy also remain in complete remission (CR). These results compare favorably with our 34% disease-free survival (DFS) in 15 allogeneic ALL transplant patients and 21% DFS in 19 patients on standard maintenance after a common induction schedule. No relapses have occurred in the 17 NHL patients transplanted in remission (median follow-up 2 years), but the two NHL patients who developed recurrent disease before ABMT died of progressive disease after temporary responses. We conclude that this method of ABMT results in rapid reengraftment with lack of toxicity and that the conditioning treatment used shows good efficacy against disease. It is applicable in high-grade lymphoid malignancy in first remission, and our results call into question the need for marrow purging in ALL and NHL patients transplanted in first remission.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Cryopreservation; Female; Follow-Up Studies; Humans; Lymphoma, Non-Hodgkin; Male; Melphalan; Mercaptopurine; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Transplantation, Autologous

A total of 62 patients with high-risk acute lymphoblastic leukemia (ALL) were treated with fractionated total body irradiation, high-dose cytosine arabinoside and melphalan followed by bone marrow transplantation (BMT). Thirty-six patients received allogeneic and 26 autologous BMT. Eight patients were treated in CR1, 36 in CR2 (first relapse occurring on therapy for 32), seven in further CR, 10 in relapse (five early first relapse, four second relapse and one fourth relapse) and one with refractory ALL. Severe toxicity occurred in 26 of the 62 patients (42%) and 14 died (22.5%) from non-leukemic causes. The actuarial event-free survival at 3.6 years was 28% after autologous BMT and 52% after allogeneic BMT with actuarial relapse rates of 62% and 35%, respectively. The results of this pilot study seem promising for this group of poor risk ALL, but the relapse rate remains high after autologous BMT and needs to be improved.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Cytarabine; Humans; Melphalan; Pilot Projects; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Survival Analysis; Transplantation, Autologous; Transplantation, Homologous; Whole-Body Irradiation

Leukemic relapse remains a major problem after both autologous and allogeneic transplantation. In the single-arm ALL autograft study our results were very encouraging and suggest that Melph/TBI can produce disease-free survival results at least as good as with other conditioning regimens. The role of postautograft maintenance remains unclear, but we feel our results are sufficiently encouraging to justify a randomized study, particularly as we studied a group of patients with relatively poor prognoses. In our study comparing Cy and TBI with Melph and TBI in AML, we have shown a significant increase in antileukemic activity after transplantation following the latter conditioning regimen. The retrospective study of Melph/TBI in autologous versus allogenic transplantation suggested that in AML this antileukemic effect may derive from increased GvHD and is not present in the autologous setting. We hope that by increasing the intensity of our GvHD prophylaxis we can reduce the toxicity of Melph/TBI and preserve its antileukemia effect. Our experience with GM-CSF has been a little disappointing: despite facilitating neutrophil recovery, we were unable to demonstrate a clinical benefit in the treatment arm. We hope to further investigate the use of cytokine combinations in the transplant setting.

Topics: Acute Disease; Adolescent; Adult; Bone Marrow Transplantation; Combined Modality Therapy; Cyclophosphamide; England; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leukemia, Myeloid; Male; Melphalan; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Transplantation, Autologous; Whole-Body Irradiation

Although patients with multiple myeloma (MM) have improved survival with current therapies, there remains a long-term risk of treatment-associated second primary malignancies. We present a case of a patient with IgG kappa MM undergoing treatment for relapsed disease who was noted to have progressive pancytopenia. For his MM, he had previously undergone autologous stem cell transplant with high-dose melphalan and had received immunomodulatory (IMiD) agents in induction, maintenance and relapse regimens. A peripheral blood smear showed abnormal lymphoid cells, and a bone marrow biopsy revealed B-cell acute lymphoblastic leukaemia (B-ALL). He underwent intensive induction chemotherapy with plans for possible allogeneic stem cell transplant. Secondary B-ALL is a rare occurrence in patients with MM, with exposure to alkylating and IMiD agents being potential risk factors.

Topics: Antineoplastic Combined Chemotherapy Protocols; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Multiple Myeloma; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation, Autologous

Acute lymphoblastic leukemia (ALL) is associated with poor survival in older adults, and allogeneic hematopoietic cell transplant (HCT) with reduced-intensity conditioning (RIC) has been an increasingly used strategy in this population. At City of Hope we conducted a retrospective analysis of 72 patients who underwent allogeneic HCT with fludarabine and melphalan (FluMel) as the conditioning regimen between 2005 and 2018, from either a matched sibling or fully matched unrelated donor while in complete remission. Tacrolimus and sirolimus (T/S) were used as graft-versus-host disease (GVHD) prophylaxis. Overall survival and progression-free survival at 4 years post-HCT were 58% and 44%, respectively. The cumulative incidences of relapse/progression and nonrelapse mortality at 4 years were 34% and 22%, respectively. Patients with Philadelphia chromosome-positive (Ph+) ALL had a significantly lower cumulative incidence of relapse/progression (20% versus 48% for patients with Ph-negative status, P = .007). In conclusion, RIC HCT with FluMel conditioning and T/S GVHD prophylaxis was associated with favorable outcomes in patients with Ph+ ALL and should be considered as a viable consolidative therapy for adult patients with ALL.

Topics: Aged; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Sirolimus; Tacrolimus; Transplantation Conditioning; Vidarabine

Women are at high risk of hypergonadotropic hypogonadism after hematopoietic cell transplantation (HCT). Hypogonadism is universal after irradiation or busulfan. We hypothesized that reduced intensity conditioning (RIC) might protect ovarian function after HCT. We retrospectively reviewed data from patients with acute leukemia treated according to the Japan Association of Childhood Leukemia Study and nationwide multicenter study protocol. We selected 11 female patients with acute leukemia who received first HCT with RIC, had survived for three or more years after HCT, and were aged ≥ 12 years at the last follow-up visit. Median age at diagnosis, HCT, and last visit were 8, 10, and 17 years. Six patients received HLA-matched bone marrow (BM), two HLA-mismatched BM, and three cord blood. Melphalan was used as conditioning regimen in all patients. At the last visit, six of seven post-pubertal patients at transplantation recovered menstruation, and four of four patients who underwent transplantation at the pre-pubertal began menstruation. Height z scores showed no significant reduction between pre-transplant and post-transplant. No patients received growth hormone treatment. Only one recipient displayed subclinical hypothyroidism. Melphalan-based RIC may be an encouraging option for patients with acute leukemia to avoid ovarian and endocrine dysfunction after HCT.

Topics: Adolescent; Adult; Child; Child, Preschool; Female; Fertility Preservation; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Infant; Leukemia, Myeloid, Acute; Melphalan; Menstruation; Ovary; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Transplantation Conditioning

The optimal conditioning regimen for elderly patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT) remains unclear. We retrospectively analyzed 1607 patients aged 50 years or older with acute myeloid leukemia (AML), acute lymphoblastic leukemia, or myelodysplastic syndrome (MDS) who underwent allo-HCT using fludarabine/busulfan (FB) or fludarabine/melphalan (FM) between 2007 and 2014. We compared the clinical outcomes among FB2 (busulfan at 6.4 mg/kg iv, n = 463), FB4 (busulfan at 12.8 mg/kg iv, n = 721), and FM140 (melphalan at 140 mg/m

Topics: Aged; Aged, 80 and over; Busulfan; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Survival Analysis; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine

Increasing numbers of patients are receiving haplo-identical stem cell transplantation (haplo-SCT) for treatment of acute leukemia with reduced intensity (RIC) or myeloablative (MAC) conditioning regimens. The impact of conditioning intensity in haplo-SCT is unknown.. We performed a retrospective registry-based study comparing outcomes after T-replete haplo-SCT for patients with acute myeloid (AML) or lymphoid leukemia (ALL) after RIC (n = 271) and MAC (n = 425). Regimens were classified as MAC or RIC based on published criteria.. A combination of post-transplant cyclophosphamide (PT-Cy) with one calcineurin inhibitor and mycophenolate mofetil (PT-Cy-based regimen) for graft-versus-host disease (GVHD) prophylaxis was used in 66 (25%) patients in RIC and 125 (32%) in MAC groups. Patients of RIC group were older and had been transplanted more recently and more frequently for AML with active disease at transplant. Percentage of engraftment (90 vs. 92%; p = 0.58) and day 100 grade II to IV acute GVHD (24 vs. 29%, p = 0.23) were not different between RIC and MAC groups. Multivariable analyses, run separately in AML and ALL, showed a trend toward higher relapse incidence with RIC in comparison to MAC in AML (hazard ratio (HR) 1.34, p = 0.09), and no difference in both AML and ALL in terms of non-relapse mortality (NRM) chronic GVHD and leukemia-free survival. There was no impact of conditioning regimen intensity in overall survival (OS) in AML (HR = 0.97, p = 0.79) but a trend for worse OS with RIC in ALL (HR = 1.44, p = 0.10). The main factor impacting outcomes was disease status at transplantation (HR ≥ 1.4, p ≤ 0.01). GVHD prophylaxis with PT-Cy-based regimen was independently associated with reduced NRM (HR 0.63, p = 0.02) without impact on relapse incidence (HR 0.99, p = 0.94).. These data suggest that T-replete haplo-SCT with both RIC and MAC, in particular associated with PT-Cy, are valid options in first line treatment of high risk AML or ALL.

Topics: Acute Disease; Adult; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytarabine; Disease-Free Survival; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid; Male; Melphalan; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Transplantation Conditioning; Treatment Outcome

Primary graft failure occurred after cord blood transplantation for a patient with acute lymphoblastic leukemia. The second transplantation was performed using haploidentical peripheral blood. The conditioning regimen consisted of fludarabine (day -1; 30 mg/m(2)), cyclophosphamide (day -1; 2,000 mg/m(2)), and total body irradiation (day -1; 2 Gy). The immunosuppressants contained tacrolimus, prednisolone, and rabbit anti-thymocyte globulin (day -3 to -2; total dose: 3.75 mg/kg). The engraftment was confirmed on day 9. Both acute and chronic graft-versus-host disease were controllable. The present regimen appears to be suitable for immediate management, fast engraftment, and the durable control of complications.

Topics: Graft vs Host Disease; Haplotypes; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Melphalan; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine

The conventional conditioning regimen for patients with leukemia prior to allogeneic stem cell transplantation is myeloablation to eradicate residual leukemic cells and host immunocompetent cells. This helps prevent leukemic relapse as well as rejection after transplantation. A myeloablative conditioning regimen with busulfan (BU) or total body irradiation (TBI) is effective for eradication of leukemic cells but is also associated with significant toxicities in the acute or late phase in pediatric patients. In an effort to minimize these adverse effects, we conducted bone marrow transplantation (BMT) from unrelated volunteer donors using a conditioning regimen without BU or TBI.. Ten patients with acute leukemia in first or second remission were given a "non-BU, non-TBI conditioning regimen," which consisted of fludarabine (FLU), cytarabine (CA), and melphalan (L-PAM) after FLAG combined with L-PAM.. Engraftment was obtained in all patients, and two patients died of relapse. Eight of 10 patients have been disease-free for a median of 126 months (116-142) after transplantation. The overall survival, event-free survival, relapse rate, and treatment-related mortality were 80.0%, 80.0%, 20.0% and 0.0%, respectively. In female patients, spontaneous menstruation with normal luteinizing hormone (LH), follicle stimulating hormone (FSH), and estradiol (E2) levels was observed in all four patients at post-pubertal age.. This conditioning regimen of FLAG combined with L-PAM (which did not contain BU and TBI) was associated with good outcomes and minimal late adverse effects in children with acute leukemia who have undergone allogeneic BMT from unrelated volunteer donors.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Busulfan; Child; Child, Preschool; Combined Modality Therapy; Cytarabine; Female; Follow-Up Studies; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Humans; Infant; Infant, Newborn; Leukemia, Myeloid, Acute; Male; Melphalan; Neoplasm Recurrence, Local; Postoperative Complications; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Remission Induction; Survival Rate; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Whole-Body Irradiation

We examined the efficacy of reduced-intensity conditioning (RIC) and compared outcomes of 93 patients older than 16 years after RIC with 1428 patients receiving full-intensity conditioning for allografts using sibling and unrelated donors for Philadelphia-negative acute lymphoblastic leukemia (ALL) in first or second complete remission. RIC conditioning included busulfan 9 mg/kg or less (27), melphalan 150 mg/m(2) or less (23), low-dose total body irradiation (TBI; 36), and others (7). The RIC group was older (median 45 vs 28 years, P < .001) and more received peripheral blood grafts (73% vs 43%, P < .001) but had similar other prognostic factors. The RIC versus full-intensity conditioning groups had slightly, but not significantly, less acute grade II-IV graft-versus-host disease (39% vs 46%) and chronic graft-versus-host disease (34% vs 42%), yet similar transplantation-related mortality. RIC led to slightly more relapse (35% vs 26%, P = .08) yet similar age-adjusted survival (38% vs 43%, P = .39). Multivariate analysis showed that conditioning intensity did not affect transplantation-related mortality (P = .92) or relapse risk (P = .14). Multivariate analysis demonstrated significantly improved overall survival with: Karnofsky performance status more than 80, first complete remission, lower white blood count, well-matched unrelated or sibling donors, transplantation since 2001, age younger than 30 years, and conditioning with TBI, but no independent impact of conditioning intensity. RIC merits further investigation in prospective trials of adult ALL.

Topics: Adolescent; Adult; Aged; Busulfan; Disease-Free Survival; Female; Graft vs Host Disease; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multivariate Analysis; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Registries; Remission Induction; Siblings; Survival Analysis; Tissue Donors; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Whole-Body Irradiation; Young Adult

Topics: Antineoplastic Agents, Alkylating; Female; Gene Rearrangement; Hematopoietic Stem Cell Transplantation; Histone-Lysine N-Methyltransferase; Humans; Melphalan; Middle Aged; Multiple Myeloma; Myeloid-Lymphoid Leukemia Protein; Neoplasms, Second Primary; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Acute lymphoblastic leukemia (ALL) with high-risk features has a poor prognosis in adults despite aggressive chemotherapy. Reduced-intensity conditioning (RIC) is a lower toxicity alternative for high-risk patients requiring hematopoietic cell transplantation (HCT); however, it has not been widely used for ALL. We conducted a retrospective study of 24 high-risk adult ALL patients who received an RIC regimen of fludarabine (Flu)/melphalan (Mel) prior to allogeneic peripheral blood stem cell transplantation (PBSCT) between 6/14/02 and 6/15/07 at the City of Hope. Indications for the RIC regimen were: (1) aged 50 years or older (42%), (2) compromised organ function (54%), or (3) recipient of a previous HCT (37.5%). Patients had a median age of 47.5 years and the median follow-up was 28.5 months for living patients. Both overall survival (OS) and disease-free survival (DFS) at 2 years was 61.5%. Relapse incidence was 21.1% and nonrelapse mortality (NRM) was 21.5% at 2 years. Chronic graft-versus-host (cGVHD) developed in 86% of evaluable patients. In this series, no significant correlations were made between outcomes and patient age, presence of Philadelphia chromosome, relatedness of donor source, or prior HCT. These high survival rates for high-risk ALL patients following RIC HCT may offer a promising option for patients not eligible for a standard myeloablative transplant.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Combined Modality Therapy; Dasatinib; Disease-Free Survival; Drug Administration Schedule; Female; Follow-Up Studies; Graft Survival; Graft vs Host Disease; Humans; Imatinib Mesylate; Male; Melphalan; Middle Aged; Myeloablative Agonists; Neoplasms, Second Primary; Peripheral Blood Stem Cell Transplantation; Piperazines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrimidines; Reoperation; Retrospective Studies; Risk; Thiazoles; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Young Adult

Topics: Antineoplastic Agents, Alkylating; Combined Modality Therapy; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Leukemia, Myeloid; Lymphoma, Non-Hodgkin; Melphalan; Multiple Myeloma; Myeloablative Agonists; Neoplasms; Neoplasms, Germ Cell and Embryonal; Neuroblastoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Toxicity associated with immunosuppression and conditioning regimens represents a common cause of neurological complications after allogeneic stem cell transplantation.. We present a 56-year-old female patient with refractory acute lymphoblastic leukemia undergoing reduced-intensity conditioning with fludarabine, BCNU and melphalan followed by matched-sibling allogeneic stem cell transplantation. Under immunosuppressive treatment with cyclosporine A (CSA) the patient developed early-onset (day +33) and ultimately fatal leukoencephalopathy.. As fludarabine and CSA represent two key substances of today's reduced-intensity conditioning regimens we raise the question of whether CSA, fludarabine or a combination of both led to this outcome and discuss differential diagnoses.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Combined Modality Therapy; Cyclosporine; Demyelinating Diseases; Fatal Outcome; Female; Humans; Immunosuppressive Agents; Melphalan; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk Assessment; Stem Cell Transplantation; Vidarabine

We report the clinical courses of two cases with relapsed acute lymphoblastic leukemia (ALL) after allogeneic bone marrow transplantation (BMT). After reinduction chemotherapy, the patients received reduced-intensity stem cell transplantation using allogeneic peripheral blood stem cells harvested from their previous BMT donors. The conditioning regimen used consisted of fludarabine and melphalan. Graft-versus-host disease (GVHD) prophylaxis was performed with low dose cyclosporin A (CsA, 1 mg/kg/day d.i.v.) on its own. The regimen related toxicity was minimal, and stable engraftment was achieved. Since acute GVHD had not developed by day 30, CsA was stopped abruptly in both cases. After CsA withdrawal, acute GVHD developed, and subsequent chronic GVHD. One of two cases is alive without any relapse of the leukemia 40 months after the peripheral blood stem cell transplantation (PBSCT). In the other case, ALL relapsed 15 months after the PBSCT, however, complete remission was again induced concomitantly with reactivated GVHD. In both these cases, the results suggest that using PBSC as a stem cell source and abrupt cessation of GVHD prophylaxis provided a potent graft-versus-leukemia effect.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child, Preschool; Cyclosporine; Graft vs Host Disease; Humans; Infant; Male; Melphalan; Peripheral Blood Stem Cell Transplantation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Tissue Donors; Transplantation Conditioning; Vidarabine

A multicenter comparative study was carried out to investigate the efficacy and safety of hematopoietic stem cell transplantation with conditioning regimens containing melphalan in pediatric patients with acute lymphoblastic leukemia. One hundred twenty three patients at a variety of remission stages were eligible for study participation. Eighty-nine were transplanted with allogeneic grafts and 34 patients with autologous grafts (23 cases with bone marrow and 11 cases with peripheral blood stem cells). Conditioning regimens used were as follows: (A) melphalan and busulfan for 40 patients, (B) melphalan, busulfan and TBI for 44 patients, (C) other regimens for 39 patients. To accelerate engraftment G-CSF (lenograstim) was administered as a 1-hour or 24-hour drip infusion daily at 5 micrograms/kg from day 5 until hematological recovery. The five year disease free survival (DFS) was 63% for 42 patients at CR 1, 41% for 41 patients at CR 2 and 33% for 40 patients at other stages. There was no significant difference in the DFS between allogeneic-transplantation and autologous-transplantation in all disease stages. In patients at remission stage for CR 1 and CR 2, the 5-year DFS by conditioning regimen was 63% for regimen (A), 54% for regimen (B) and 54% for regimens with melphalan and TBI. There was no significant difference in the DFS between the groups. Serious complications such as renal failure were observed in 11%, veno-occlusive disease in 9%, and interstitial pneumonia in 9%. The most dominating cause of death was relapse in the disease (48% of deaths) which was most commonly observed in autologous transplantation. Contrary to that, treatment related toxic death was the most frequent cause of deaths in allogeneic-transplantation.

Topics: Child; Child, Preschool; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Melphalan; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation Conditioning

Eight children developed osteochondroma (OS) at a mean of 88 months after hematopoietic stem cell transplantation (HSCT). The mean age at HSCT was 56 months (12-84). This represents a cumulative incidence of 20% among patients less than 18 years of age transplanted from 1981 to 1997. These eight patients underwent allogeneic (n = 2) or autologous (n = 6) transplantation for either acute leukemia (n = 6) or neuroblastoma (n = 2) after a conditioning regimen including TBI (n = 7) or a combination of Bu and CY. OS was multiple in seven patients and solitary in one. Eight lesions were resected and all were benign. Four children received growth hormone before diagnosis of OS, but there was no clinical, radiological or histological difference between those who did not. Univariate analysis showed an increased rate associated only with autologous HSCT, with a 31.7% probability of a new OS at 12 years after HSCT. Osteochondroma should be added to the other adverse effects of HSCT in children.

Topics: Actuarial Analysis; Acute Disease; Bone Neoplasms; Busulfan; Child; Child, Preschool; Cranial Irradiation; Cyclophosphamide; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Leukemia, Myeloid; Male; Melphalan; Neoplasms, Radiation-Induced; Neoplasms, Second Primary; Neuroblastoma; Osteochondroma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation Conditioning; Whole-Body Irradiation

We describe two cases of severe constrictive pericarditis arising after allogeneic BMT conditioning involving total body irradiation and melphalan to treat Philadelphia-chromosome positive ALL. Both patients required pericardectomy, resulting in marked improvement in ventricular filling. However, a degree of right-sided cardiac failure persisted in both patients secondary to restrictive cardiomyopathy. Constrictive pericarditis has not been previously described after BMT, but has been observed following thoracic radiotherapy for malignancy, usually involving a substantially higher radiation dose. Pericardial constriction and restrictive cardiomyopathy should be considered as causes of breathlessness and/or oedema occurring late after BMT. Bone Marrow Transplantation (2000) 25, 571-573.

Topics: Adult; Antineoplastic Agents, Alkylating; Bone Marrow Transplantation; Combined Modality Therapy; Edema; Escherichia coli Infections; Fatal Outcome; Humans; Male; Melphalan; Pericardiectomy; Pericarditis, Constrictive; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation Conditioning; Transplantation, Homologous; Whole-Body Irradiation

Topics: Adult; Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Bone Marrow Transplantation; Combined Modality Therapy; Daunorubicin; Humans; Liposomes; Male; Melphalan; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Retreatment; Time Factors; Transplantation Conditioning; Transplantation, Homologous

Topics: Adolescent; Adult; Antineoplastic Agents, Alkylating; Blood Component Removal; Combined Modality Therapy; Disease-Free Survival; Female; Granulocyte Colony-Stimulating Factor; Hematologic Neoplasms; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Multiple Myeloma; Portugal; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies

Thirty children with leukemia underwent allogeneic bone marrow transplantation (BMT) following a radiation-free preparative regimen, from July 1988 to January 1996. Twelve males and 18 females, ages 9 months to 15 years (median 8.5 years), received busulfan (BU, 4 mg/kg/day for 4 days by mouth), followed by melphalan (L-PAM, 60-70 mg/m2/day i.v. for 3 days), and infusion of allogeneic marrow from an HLA-matched related donor. Diagnoses included acute myelogenous leukemia (n = 20), acute lymphoblastic leukemia (n = 8) and chronic myelogenous leukemia (n = 2). Twenty-five patients were transplanted in first complete remission (CR), three in second CR, and two patients with chronic myelogenous leukemia in the first chronic phase. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate (MTX) alone in 27 patients and short-term MTX and cyclosporin A in three patients. Engraftment was achieved in all patients. Toxicities were mild or moderate. Six patients developed acute GVHD: four had grade I and two had grade II. Chronic GVHD was documented in eight patients. Three patients relapsed. As of September 1997, 27 patients were alive and well at 22-110 months (median 61) of follow-up. The disease-free survival rate at 5 years after BMT was 90%. A regimen consisting of high-dose BU and L-PAM without total body irradiation is useful for conditioning for allogeneic BMT in children with leukemia.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Busulfan; Child; Child, Preschool; Female; Glucocorticoids; Graft vs Host Disease; Growth; Humans; Infant; Leukemia, Myeloid, Acute; Male; Melphalan; Methylprednisolone; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation, Homologous

To investigate the effect of MAC conditioning regimen on endocrine glands function in leukemia patients after bone marrow transplantation(BMT).. Thyroid and adrenocortical functions were assayed by radioimmunoassay (RIA) in 26 leukemia patients before and after BMT.. All patients had normal thyroid and adrenocortical functions before BMT. As compared with that pre BMT, the median serum TSH levels were increased at 1, 3 and 6 months post BMT(P < 0.01). This thyroid dysfunctions were found in 7 of 26 patients, 6 of whom were recovered at 6 months post BMT.. There was little effect of MAC conditioning regimen on adrenocortical function. Thyroid dysfunctions were found in 28% of the patients after BMT, and normalized in a short period without replacement therapy.

Topics: Adolescent; Adrenal Cortex; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Cyclophosphamide; Cytarabine; Female; Humans; Male; Melphalan; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thyroid Gland; Transplantation Conditioning

To evaluate the clinical outcome of autologous bone marrow transplantation(ABMT) in acute leukemias.. Data of 73 acute leukemia patients performed ABMT in our hospital from October 1986 to December 1997 were retrospectively analyzed. The median age was 25.5(9-48) years. Forty-three of them were ANLL [CR1 35, CR2 or early relapse (ER)8], 30 were ALL (CR1 25, CR2 or ER 5). Conditioning regimens were CTX 120 mg/kg + STBI 9-10 Gy or Bu 16 mg/kg or Mel 160-180 mg/m2 + Ara-C 4 g/m2.. All patients engrafted successfully. The median follow-up duration was 806 (32-3400) days. The 3-year probabilities of disease-free survival (DFS) for ANLL and ALL in CR1 were 54.9 +/- 7.7% and 67.0% +/- 10.6%, respectively, and the probabilities of relapse were 39.3% +/- 9.3% and 23.7% +/- 10.6%, respectively.. To decrease relapse and increase DFS, patients with acute leukemia in CR1 who have no HLA-matched related donor are recommended for ABMT.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Female; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

It is vital to develop effective therapy for children with acute lymphoblastic leukemia (ALL), in whom no remission occurs or who suffer relapse with current protocols. Cellular drug resistance is thought to be an important cause of induction failure and relapse. We performed in vitro tests of bone marrow samples in 196 children with newly diagnosed ALL with a 4-day culture and a methyl-thiazol-tetrazolium assay. We tested 16 drugs and calculated the 70% lethal dose (LD70) for 14 drugs and the leukemic cell survival (LCS) rate for dexamethasone and prednisolone. For each single drug, patients were classified into two groups, sensitive or resistant, by median concentration of LD70 or LCS. When patients were classified into three groups by sensitivity to four drugs of DPAV (dexamethasone, prednisolone, L-asparaginase, and vincristine), 3-year event-free survival (EFS; 95% confidence intervals) of the super sensitive group (SS; sensitive to all 4 drugs) was 0.833 (0.690 to 0.976), that of the intermediate sensitive group (IS; sensitive to 2 or 3 drugs) was 0.735 (0.609 to 0.863), and that of the relatively resistant group (RR; sensitive to no drugs or to 1 drug) was 0.541 (0.411 to 0.670; P = .0008). We then investigated the relationship between the above four-drug sensitivity and the time of relapse. The SS and IS patients tended to maintain continuous complete remission, and RR patients tended to undergo induction failure and early and late relapse (P = .004). Initial white blood cell count, immunologic classification, and age were also predictive factors, but the patient numbers showed no statistical correlation between these factors and the four-drug sensitivity groups (SS, IS, and RR). When we took three groups SS/IS/RR and investigated the EFS for various clinical groups, DPAV sensitivity strongly influenced EFS in the standard-risk ALL (P = .016). In vitro drug sensitivity testing provides additional prognostic information about childhood ALL, and early detection of drug resistance at the time chemotherapy commences may provide a successful strategy for individualizing treatment, as the results indicate de novo resistance to front-line drugs and suggest alternative, second-line drugs.

Topics: Aclarubicin; Adolescent; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bleomycin; Bone Marrow; Cell Survival; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Disease-Free Survival; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Etoposide; Follow-Up Studies; Humans; Infant; Infant, Newborn; Life Tables; Melphalan; Methotrexate; Mitomycin; Mitoxantrone; Neoplastic Stem Cells; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prognosis; Recurrence; Remission Induction; Tumor Cells, Cultured; Vincristine

Causes of treatment-related death were studied amongst 138 patients with acute myeloid (n = 90) or lymphoblastic (n = 48) leukemia allografted from HLA-identical siblings in first (n = 107) or second (n = 31) remission after a conditioning regimen comprising 110 mg/m2 melphalan and 1050 cGy single-fraction total-body irradiation (TBI) prescribed as maximum lung dose. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine (n = 78) or cyclosporine-methotrexate (n = 60). Eighty-one patients died of causes other than relapse 16-2917 days (median 77) after transplantation. The actuarial probability of non-relapse mortality was 62% at 5 years. The major primary causes of death were pneumonitis (n = 38, 47%), GVHD (n = 18, 22%), and sepsis (n = 11, 14%). Pneumonitis contributed to 42 of the deaths (52%), and its etiology was infective (n = 27), idiopathic (n = 14), or a combination of the two (n = 1). On multivariate analysis, GVHD prophylaxis with cyclosporine alone was associated with a higher overall toxic death rate. The use of cyclosporine alone and a low infused cell dose (<2.5 x 10(8) total nucleated cells/kg or <0.6 x 10(8) mononuclear cells/kg) were associated with a higher risk of death from pneumonitis. We conclude that the use of cyclosporine alone as GVHD prophylaxis is associated with increased transplant-related toxicity, and the addition of methotrexate and infusion of a higher number of cells decrease the incidence of fatal pneumonitis.

Topics: Acute Disease; Adolescent; Adult; Antineoplastic Agents, Alkylating; Bone Marrow Transplantation; Child; Child, Preschool; Female; Graft vs Host Disease; Humans; Leukemia, Myeloid; Lung Diseases, Interstitial; Male; Melphalan; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sepsis; Transplantation Conditioning; Whole-Body Irradiation

To explore more effective and less toxic conditioning regimen without total body irradiation for autologous bone marrow transplantation (ABMT) for acute leukemia (AL).. Twenty patients with AL were treated with ABMT, including 13 cases of acute myelocytic leukemia (AML) and 7 cases of acute lymphocytic leukemia (ALL). A median of 1.06 (range, 0.69-1.75) x 10(8) nucleated BM cells/kg was harvested and stored in normal salt solution containing heparin at 4 degrees C. The conditioning regimen (MAC) consisted of high-dose melphalan (M, 140-160 mg/m2), cyclophosphamide (CY, 120 mg/kg) and cytosine arabinoside (Ara-C, 2.0 g/m2). These 3 drugs were administered within 25 hours and the unpurged autologous marrow infusion began after another 24-hour interval.. MAC regimen could result in myeloblastic efficacy in a week. All marrow cells were reinfused within 56 hours after the harvest so that hemopoietic reconstitutions could occur in all the patients. The median time to reach a neutrophil count of > 1.0 x 10(9)/L and a platelet count of > 50 x 10(9)/L was 20 and 26 days respectively. With a median observation period of 25 months, the median duration on continuous complete remission in our patients was 22 months, and the longest reached 56 months. The median survival was 33 months, and the longest was over 6 years. The event-free survival at 2 years had reached 72%. In seven patients with leukemic relapse, six (86%) relapsed within 8 months after ABMT. The relapse rate and mortality in AML patients were significantly lower than those in ALL patients. In 7 patients with M3, relapse had not yet been observed. The nonhematologic toxic effects of MAC conditioning regimen occurred mainly in the gastrointestinal tract.. The preliminary results indicated that the ABMT using MAC conditioning regimen had some advantages in stronger antileukemic efficacy, less extrahematologic toxicity and earlier recovery of platelet and could greatly prolong the duration of remission and survival in some patients with AL.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Bone Marrow Transplantation; Cyclophosphamide; Cytarabine; Female; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Male; Melphalan; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Forty-four adults with AML (n = 18) or ALL (n = 26) beyond first remission underwent unpurged (n = 39) or purged (n = 5) autografting after 110-140 mg/m2 melphalan and 1050 cGy TBI. ALL patients were eligible to receive maintenance chemotherapy with 6-mercaptopurine and methotrexate for 2 years after hematologic recovery. The duration of first remission was 1-167 months (median 11). The median time to 50 x 10(9)/I platelets was 76 days, and that to 0.5 x 10(9)/I neutrophils 31 days. Eight patients died of transplant-related toxicity; seven within 1 year. Twenty-two patients relapsed at 1-20 months (median 2.5 months). The 3-year probabilities (95% CI) of relapse and disease-free survival are 58% (43-75%) and 31% (17-45%), respectively. The duration of the first remission (< 1 year vs > or = 1 year) and the stage of transplant (second remission vs other) had no effect on relapse or disease-free survival. There was a trend towards higher relapse rates (76 vs 34%) and poorer disease-free survival (19 vs 49%) among ALL patients compared with AML which did not reach significant levels due to small patient numbers. We conclude that melphalan-TBI is a suitable conditioning regimen for autografting in advanced leukemia. The outcome of AML patients is comparable to standard regimens, but the outcome of ALL patients is poor and measures to enhance the anti-leukemic efficacy are necessary.

Topics: Acute Disease; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Bone Marrow Transplantation; Combined Modality Therapy; Disease-Free Survival; Female; Humans; Leukemia; Leukemia, Myeloid; Male; Melphalan; Mercaptopurine; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Salvage Therapy; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Whole-Body Irradiation

Children with acute lymphoblastic leukemia (ALL) undergoing allogeneic bone marrow transplantation (BMT) using total body irradiation (TBI)-containing conditioning regimens are at risk of substantial late sequelae affecting growth and endocrine functions. This has lead to the use of non-TBI or chemotherapy conditioning regimens for ALL patients in many centers. However, it is unknown whether chemotherapy conditioning results in improved antileukemic efficacy or reduced transplant-related toxicity. We report our experience using a chemotherapy conditioning regimen (busulfan (Bu), cyclophosphamide (CY) and melphalan (Mel)) in 26 consecutively enrolled children with ALL (group I). At a median follow-up of 58 months, event-free survival (EFS) for Bu/CY/Mel-treated patients was 27% (+/- 8.7), while the leukemic relapse rate was 49% (+/- 13). Regimen-related toxicity was severe in these patients: overall treatment-related mortality was 42%, while 50% of patients had interstitial pneumonitis and 35% of patients had severe hemorrhagic cystitis. A historical control group of 25 consecutively enrolled patients, mostly treated with TBI-containing regimens (group II), had an EFS of 36% (+/- 9.6%) and a leukaemic relapse rate of 45% (+/- 11) at a median follow-up of 117 months. We conclude that the Bu/CY/Mel conditioning regimen leads to severe transplant-related toxicity and did not significantly improve leukemic relapse rates.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Busulfan; Child; Child, Preschool; Cyclophosphamide; Humans; Infant; Melphalan; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation Conditioning; Transplantation, Homologous

Chemotherapy induces high remission rates in high-grade lymphoma. However relapse remains a major problem. One approach to this is myeloablative chemotherapy with transplantation of autologous bone marrow or peripheral blood progenitor cells (PBPC). Immunological mechanisms have been suggested to play a role in the prevention of relapse after transplantation. We investigated the recovery of cellular immune functions after high-dose chemotherapy and PBPC transplantation in 5 patients with high grade non-Hodgkin's lymphoma. All patients showed rapid reconstitution of natural killer (NK) and inducible lymphokine-activated killer (LAK)-activity 10-14 days after transplantation. Four of 5 patients showed higher levels of LAK-generation in the post-transplant period compared with levels prior to myeloablative treatment. Absolute lymphocyte counts in peripheral blood reached 1.0 x 10(9)/l between days 10 and 13 with a predominance of CD8+ cells and an inversion of the CD4/CD8 ratio. Four of 5 patients had a transient increase in CD56+ and CD16+ cell counts post-transplant. No change in the proportion of CD25+ cells was noted. These results show that PBPC transplantation leads to a rapid recovery of cellular immune functions after myeloablative chemotherapy and provides evidence for an increased presence of LAK precursor cells early in the post-transplant period which can be activated by IL-2 to exert high levels of cytotoxicity.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Marrow Diseases; Busulfan; Carmustine; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Doxorubicin; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Killer Cells, Lymphokine-Activated; Killer Cells, Natural; Leukapheresis; Lymphocyte Count; Lymphocyte Subsets; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Male; Melphalan; Mesna; Middle Aged; Podophyllotoxin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Time Factors; Treatment Outcome; Vincristine

Between 1983 and 1993, 42 patients with acute lymphoblastic leukemia (ALL) in second complete remission (CR) underwent an allogeneic HLA-identical bone marrow transplant (BMT; there was one family mismatched graft). The conditioning regimens varied, consisting of cyclophosphamide (CY) and total body irradiation (TBI; n = 10); CY, TBI, Ara C, VP-16 (n = 11); TBI, Ara C, melphalan (n = 20) (TAM) or other (n = 1). Cyclosporine A (CsA) (n = 15) or CsA and methotrexate (MTX) (n = 24) were the main regimens for prophylaxis of graft-versus-host disease (GVHD). Nineteen of 42 patients are alive in CR ranging from 1 to 72 months after BMT with a median follow-up of 36 months. The 4-year actuarial survival rate was 53%. The actuarial relapse rate was 17%. Twenty three patients died: 4 patients of leukemic relapse, 9 of infection, 2 of acute GVHD, 2 of multiorgan failure after chronic GVHD, 2 of a secondary tumour and 4 patients died of other causes. Several pre- and post-transplant characteristics were analyzed to determine predictive factors for survival, relapse and GVHD. The relapse rate was significantly influenced by the type of conditioning regimen with no relapse in the TBI, Ara C, melphalan group. The analysis of long-term sequelae shows that there are no severe complications in this last group. Our results confirm that allogeneic BMT can lead to long-term survival for children with ALL in second CR and suggest an advantage of using the TAM conditioning regimen in the eradication of the leukemic disease.

Topics: Actuarial Analysis; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Cause of Death; Child; Child, Preschool; Combined Modality Therapy; Cyclosporine; Cytarabine; Disease-Free Survival; Female; Follow-Up Studies; Graft vs Host Disease; Humans; Male; Melphalan; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Retrospective Studies; Survival Analysis; Treatment Outcome; Whole-Body Irradiation

Conditioning regimens for allogeneic bone marrow transplantation are designed to eradicate malignant cells and to provide sufficient immunosuppression for engraftment of donor marrow. Total body irradiation and high-dose cyclophosphamide are the most established immunosuppressive agents used for this purpose. It is uncertain whether other alkylating agent-based conditioning regimens are sufficiently immunosuppressive to allow engraftment of allogeneic marrow. We report four patients who had prompt engraftment after conditioning with melphalan-based chemotherapy regimens (BEAM or busulfan/melphalan). Two patients survived without disease for a prolonged period, indicating that these melphalan regimens are sufficiently immunosuppressive to allow sustained engraftment and donor hematopoiesis.

Topics: Adult; Bone Marrow Transplantation; Female; Graft Rejection; Hodgkin Disease; Humans; Male; Melphalan; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Cyclosporine; Etoposide; Graft vs Host Disease; Humans; Male; Melphalan; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Whole-Body Irradiation

Thirty-eight patients with poor risk ALL in first remission received maintenance chemotherapy following ABMT. Patients were conditioned for ABMT with high-dose melphalan and single fraction total body irradiation. Maintenance chemotherapy was commenced in a total of 26 patients and was tolerated to a median daily dose of 6-mercaptopurine of 40.5 mg/m2 and a median weekly dose of MTX 8.3 mg/m2. Twenty patients remain alive in first remission with a projected disease-free survival of 50% and a median follow-up in survivors of 200 weeks (range 48-387 weeks). Eleven patients have relapsed at a median of 4.5 months from ABMT. These patients were compared with remission patients with ALL receiving conventional chemotherapy on the United Kingdom Medical Research Council trials UKALL X and XA. After stratifying for major risk factors and allowing for the delay from remission to transplant, we have shown a significant reduction in the risk of relapse after ABMT (p = 0.04). Disease-free survival was not significantly increased due to transplant-related toxicity. This study suggests that maintenance chemotherapy to prevent relapse after ABMT for ALL is well tolerated and warrants assessment in a formal controlled trial.

Topics: Adolescent; Adult; Bone Marrow Transplantation; Child; Child, Preschool; Clinical Trials as Topic; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Humans; Male; Melphalan; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Whole-Body Irradiation

The aim of this paper was to present the results of bone marrow harvest followed by cryopreservation in 22 children with various malignant diseases, and the clinical course of autologous bone marrow transplantation (ABMT) performed in 10 children (three with acute lymphoblastic leukemia (ALL), three with acute myeloblastic leukemia (AML) and four neuroblastoma stage IV (NB)). In 20/22 children the harvested bone marrow contained a sufficient number of granulocyte-macrophage-colonyforming units (GM-CFU) for later marrow reinfusion. Hematological reconstitution was obtained in all 10 children who underwent ABMT. No child died of toxicity. The median time to neutrophil count > 0.5 x 10(9)/l, thrombocyte count > 50 x 10(9)/l and to discharge from hospital were 34, 49 and 29 days respectively. Five children are alive with no evidence of active disease 11-21 months after ABMT. Five children have suffered relapse and have died. It was concluded that sufficient amounts of precursor bone marrow cells may be harvested in children during a pause in cystostatic therapy. The acute toxicity of ABMT in children with malignant diseases was only moderate.

Topics: Adolescent; Bone Marrow Purging; Bone Marrow Transplantation; Busulfan; Child; Cryopreservation; Cyclophosphamide; Female; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Melphalan; Neuroblastoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation, Autologous

We prospectively analyzed minimal residual disease (MRD) in four patients with B-cell precursor acute lymphoblastic leukemia who had been in complete remission for more than one year after chemotherapy and allogenic or autologous bone marrow transplantation (BMT). MRD was quantitatively estimated using polymerase chain reaction amplification to detect the complementarity-determining region III of the immunoglobulin heavy chain gene at limiting dilution DNA samples. Our study showed that remission induction chemotherapy reduced at most 2-logs of leukemia cells, and that subsequent consolidation chemotherapy induced further reduction of leukemia cells. In two cases, 10(-5) levels of MRD were detected two months after BMT. However, no MRD was detected four months after BMT. We also showed the effectiveness of ex vivo purging with anti-CALLA monoclonal antibodies which eliminated at least 2-logs of leukemia cells in autologous BMT. Our results suggest that this detection system is useful for assessing the reduction of the original leukemia clone, and that the presence of MRD within three months after BMT is not related to clinical outcome.

Topics: Antineoplastic Combined Chemotherapy Protocols; Base Sequence; Bone Marrow; Bone Marrow Transplantation; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Genes, Immunoglobulin; Humans; Immunoglobulin Heavy Chains; Melphalan; Molecular Sequence Data; Polymerase Chain Reaction; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Prospective Studies; Transplantation, Autologous; Transplantation, Homologous; Whole-Body Irradiation

High dose melphalan (HDM 110-140 mg/m2) and total body irradiation (TBI, 10.5 Gy, single fraction) followed by infusion of autologous bone marrow (ABMT) was evaluated for toxicity and efficacy in 24 children with acute lymphoblastic leukaemia (ALL) in second (CR2) or third remission (CR3). Marrow was purged with Campath 1 in six children (four were children in CR3). All children had engraftment with a median of 30 days (range 18-70 days) to neutrophil count greater than 0.5 x 10(9)/l. Four children (16%) died from toxicity 1-4 months after autograft, two from pneumonitis, one from an intracerebral haemorrhage and one from sepsis. Apart from fever and mucositis the procedure was well tolerated. Nine of 17 children treated in CR2 remain in complete remission 6-72 months after ABMT (median 25 months). Seven of these have a follow-up of greater than 12 months. Three of the seven children treated in CR3 are alive 17, 22 and 29 months post ABMT. Seven children relapsed within 10 months (median 4 months) of the autograft. Only one relapse has occurred beyond 10 months. HDM and TBI followed by ABMT is a relatively well tolerated regimen and may contribute to survival in children with relapsed ALL.

Topics: Adolescent; Bone Marrow Transplantation; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Male; Melphalan; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation, Autologous; Whole-Body Irradiation

The technique of total body irradiation (TBI) developed at Istituto Nazionale Tumori, Milan, Italy, is described. This technique consists of i) administration of 12.5 Gy and 14.85 Gy TBI for autologous and allogeneic bone marrow transplantation respectively; ii) in all cases in vivo dosimetry of absorbed TBI dose; and iii) radiation doses to lungs higher than previously described. As of June 1988, seventeen patients with Hodgkin's disease and four with lymphoblastic lymphoma received TBI and 120-180 mg/m2 melphalan. Respiratory function was prospectively evaluated demonstrating moderate and transient reduction of pulmonary function.

Topics: Adolescent; Adult; Bone Marrow Transplantation; Child; Combined Modality Therapy; Hodgkin Disease; Humans; Italy; Melphalan; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Radiotherapy Dosage; Whole-Body Irradiation