ABSTRACT
We studied the feasibility and efficacy of a two-step approach to Auto-SCT for patients with AML in second remission. Step 1 consisted of consolidation chemotherapy using cytarabine 2000 mg/m(2) i.v. every 12 h for 4 days plus etoposide 40 mg/kg total dose by continuous i.v. infusion over the same 4 days. PBSC were collected after G-CSF stimulation during recovery from this chemotherapy. Step 2, auto-SCT, used a preparative regimen of oral BU 16 mg/kg over 4 days followed by etoposide 60 mg/kg i.v. Of the 50 patients entered on Step 1, two died from treatment complications, and seven failed to proceed to transplantation. A median CD34+ cell dose of 5.9 x 10(6)/kg was collected in a median of three collections. With a median follow-up of 8.2 years, 5-year disease-free survival (DFS) is 28%. The most important prognostic factor was cytogenetics, with acute promyelocytic leukemia (APL) patients having a 5-year DFS of 67% compared with 16% for others. We conclude that this two-step approach to autologous transplantation produces good CD34+ mobilization and that this approach has cured some patients. Results in patients with APL are especially promising.
Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Antineoplastic Agents, Phytogenic/therapeutic use , Cytarabine/therapeutic use , Etoposide/therapeutic use , Leukemia, Myeloid, Acute/therapy , Peripheral Blood Stem Cell Transplantation , Adult , Aged , Aging , Antigens, CD34/analysis , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/adverse effects , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/adverse effects , Combined Modality Therapy/adverse effects , Cytarabine/administration & dosage , Cytarabine/adverse effects , Disease-Free Survival , Etoposide/administration & dosage , Etoposide/adverse effects , Female , Humans , Ideal Body Weight , Infusions, Intravenous , Kaplan-Meier Estimate , Leukemia, Myeloid, Acute/classification , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Peripheral Blood Stem Cell Transplantation/adverse effects , Remission Induction , Transplantation, Autologous , Treatment Outcome , Treatment Refusal , Young AdultABSTRACT
Autologous bone marrow transplant (ABMT) and stem cell transplantation (ASCT) are important treatment modalities for acute myeloid leukemia (AML). The role of ASCT in first remission patients remains controversial. Phase II and phase III studies demonstrate that patients with favorable-risk cytogenetics benefit from ASCT, with reduction in relapse and improvement in leukemia-free survival (LFS). Patients with poor-risk cytogenetics do not appear to benefit significantly from ASCT and should preferentially be treated with allogeneic transplant. The role of ASCT for patients with intermediate risk disease is uncertain. It appears that ASCT in first remission will improve disease-free survival compared to standard chemotherapy. Sufficient patients who relapse after chemotherapy treatment can be salvaged with ASCT in second remission such that the beneficial effect on overall survival is blunted. ASCT produces equivalent results to ABMT but with reduced morbidity. The collection of stem cells during recovery from intensive dose consolidation therapy appears to be an attractive strategy that can increase the percentage of patients who are able to receive their intended transplant. Consolidation therapy prior to stem cell collection and transplant has been shown to decrease the relapse rate and improve outcomes, but the optimal nature of this consolidation therapy is unknown. For patients with AML in second remission, ABMT/ASCT offers a substantial salvage rate, and is particularly effective for patients with acute promyelocytic leukemia.
Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Leukemia, Myeloid/therapy , Acute Disease , Cytogenetic Analysis , Humans , Leukemia, Myeloid/diagnosis , Prognosis , Survival Analysis , Transplantation, Autologous , Treatment OutcomeABSTRACT
We studied the efficacy of a two-step approach to autologous stem cell transplantation for patients with advanced acute myeloid leukemia. Step 1 consisted of consolidation chemotherapy using cytarabine 2000 mg/m(2) twice daily for 4 days plus etoposide 40 mg/kg by continuous infusion over the same 4 days. Peripheral blood stem cells were collected under granulocyte colony-stimulating factor (G-CSF) stimulation during recovery from this chemotherapy. Step 2, autologous stem cell transplantation, utilized the preparative regimen of oral busulfan 16 mg/kg followed by etoposide 60 mg/kg i.v. During step 1, there were no treatment-related deaths among 28 patients, but two patients did not proceed to transplantation because of failure of mobilization. A median CD34+ dose (x10(6)/kg) of 13.6 was collected. Of 26 patients undergoing autologous transplant, there was one treatment-related death and 12 relapses. With a median follow-up of 5.4 years, 5 year event-free survival (EFS) of all patients entered is 54%. The most important prognostic factor was cytogenetic changes. All seven patients with t(15,17) remained in long-term remission whereas EFS for other patients was 38%. We conclude that this two-step approach to autologous transplantation produces excellent stem cell yields, allows a high percentage of patients to receive the intended therapy, and provides effective treatment.
Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Leukemia, Myeloid, Acute/therapy , Adult , Aged , Antigens, CD34/metabolism , Antineoplastic Combined Chemotherapy Protocols , Busulfan/administration & dosage , Cell Count , Chromosomes, Human, Pair 15 , Chromosomes, Human, Pair 17 , Cytarabine/administration & dosage , Cytogenetics , Disease-Free Survival , Etoposide/administration & dosage , Granulocyte Colony-Stimulating Factor/administration & dosage , Hematopoietic Stem Cell Mobilization/methods , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Middle Aged , Prognosis , Translocation, Genetic , Transplantation, AutologousABSTRACT
BACKGROUND: Autologous bone marrow transplantation is an important therapy for patients with acute myelogenous leukemia (AML). However, leukemia in the graft may contribute to posttransplant relapse. Treatment of the graft with 4-hydroperoxycyclophosphamide (4HC) is sometimes used to decrease numbers of infused leukemia cells (4HC purging). No large controlled trials evaluating efficacy and toxicity of 4HC purging are reported. METHODS: We studied 294 patients reported to the Autologous Blood and Marrow Registry receiving either a 4HC-purged (n = 211) or unpurged (n = 83) autograft for AML in first (n = 209) or second (n = 85) remission. Analyses were restricted to patients transplanted less than 6 months after achieving remission. Using Cox proportional hazards regression, we compared time to treatment failure (death or relapse, inverse of leukemia-free survival) after 4HC-purged vs unpurged transplants while controlling for important prognostic factors. RESULTS: Median duration of posttransplant neutropenia was 40 (range, 10-200) days after 4HC-purged transplants and 29 (9-97) days after unpurged transplants (p < 0.01). Transplant-related mortality was similar in the two groups. In multivariate analysis, patients receiving 4HC-purged transplants had lower risks of treatment failure than those receiving unpurged transplants (relative risk, 0.69, p = 0.12 in the first posttransplant year; relative risk, 0.28, p < 0.0001 thereafter). Adjusted three-year probabilities of leukemia-free survival (95% confidence interval) were 56% (47-64%) and 31% (18-45%) after 4HC-purged and unpurged transplants in first remission, respectively. Corresponding probabilities in second remission were 39% (25-53%) and 10% (1-29%). CONCLUSION: Grafts purged with 4HC are associated with higher leukemia-free survival after autologous bone marrow transplants for AML.
Subject(s)
Bone Marrow Purging/methods , Bone Marrow Transplantation/methods , Cyclophosphamide/analogs & derivatives , Leukemia, Myeloid/therapy , Acute Disease , Adolescent , Adult , Americas/epidemiology , Bone Marrow Transplantation/mortality , Child , Child, Preschool , Disease-Free Survival , Female , Graft Survival , Humans , Infant , Leukemia, Myeloid/mortality , Leukemia, Myeloid/pathology , Life Tables , Male , Middle Aged , Prognosis , Proportional Hazards Models , Registries , Remission Induction , Retrospective Studies , Risk , Survival Analysis , Transplantation, Autologous , Treatment OutcomeABSTRACT
Autologous bone marrow transplantation remains an investigational treatment for adult ALL. Despite many anecdotal studies showing efficacy, the rarity of ALL has prevented the large randomized trials necessary to confirm effectiveness. Candidates for autoBMT include adult patients in first CR with adverse risk factors and all patients who have experienced disease relapse. It remains debatable which preparative regimen is optimal, whether purging is necessary, or if chemotherapy or immunotherapy administered after transplantation can decrease disease relapse. Overall, every effort should be made to enter ALL patients on well-designed randomized multi-institutional trials. These trials should compare autologous transplantation to newer more intensive chemotherapy regimens and should take into account the heterogeneity of ALL. A quality of life analysis should be performed as one high-dose treatment may be less toxic and better tolerated than multiple cycles of consolidation chemotherapy. Strategies aimed at enhancing an autologous graft-versus-leukemia effect after transplantation may enhance long-term survival. Many more studies are needed to further define the optimal role of autoBMT in adult ALL.
Subject(s)
Hematopoietic Stem Cell Transplantation , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Transplantation, Autologous , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Marrow Purging , Bone Marrow Transplantation , Clinical Trials as Topic , Combined Modality Therapy , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Immunophenotyping , Karyotyping , Life Tables , Multicenter Studies as Topic , Organ Specificity , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Prognosis , Recurrence , Remission Induction , Risk Factors , Salvage Therapy , Survival Analysis , Transplantation Conditioning , Transplantation, Autologous/adverse effects , Treatment OutcomeABSTRACT
The role of high-dose chemotherapy (HDCT) and autologous hematopoietic stem cell rescue in breast cancer is still controversial. We analyzed the outcomes of 1111 consecutive patients with histologically proven breast cancer who underwent HDCT at 5 major California medical centers. The overall treatment-related mortality (TRM) was 2.3%. TRM was not influenced by disease stage or the HDCT regimen delivered, but it was influenced by hematopoietic graft source. The TRM was 6.1% when bone marrow with or without blood stem cells was used, but only 1.4% when blood stem cells alone were used (P < .001). With a median follow-up of 2.8 years (range, 0.1-8.2 years) after HDCT and autologous hematopoietic stem cell rescue, the estimated 5-year event-free survival (EFS) and overall survival (OS) for stage II/IIIA patients with > or =10 involved axillary lymph nodes were 67% and 76%, respectively. Patients with metastatic breast cancer (MBC) (median follow-up, 1.9 years [range, 0.03-8.3 years]) achieving a complete response (CR) to conventional-dose chemotherapy or rendered to a "no evidence of disease" status before HDCT had significantly better estimated 5-year EFS and OS (28% and 57%, respectively) than those achieving a partial response before HDCT (19% and 27%, respectively; P < or = .0001). Our data suggest that HDCT with hematopoietic stem cell rescue is safe and can be beneficial to patients with high-risk primary breast cancer and for those with MBC achieving CR/no evidence of disease.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Breast Neoplasms/drug therapy , Hematopoietic Stem Cell Transplantation , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Marrow Transplantation , Breast Neoplasms/mortality , Breast Neoplasms/therapy , California/epidemiology , Carboplatin/administration & dosage , Carmustine/administration & dosage , Cisplatin/administration & dosage , Clinical Trials, Phase II as Topic , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Disease-Free Survival , Female , Follow-Up Studies , Humans , Life Tables , Lymphatic Metastasis , Mastectomy , Mitoxantrone/administration & dosage , Multicenter Studies as Topic , Radiotherapy, Adjuvant , Retrospective Studies , Survival Analysis , Thiotepa/administration & dosage , Treatment OutcomeABSTRACT
We designed and implemented a new mitoxantrone-based high-dose chemotherapy regimen to minimize pulmonary injury (seen in carmustine-based regimens) in patients with breast cancer. One hundred and ninety-one breast cancer patients (99 stage II/IIIA; 27 stage IIIB; 65 stage IV responsive to conventional-dose chemotherapy) were treated with high-dose chemotherapy (CTM) delivered over 4 days (cyclophosphamide (6 g/m2), thiotepa (600 mg/m2), and mitoxantrone (24-60 mg/m2)) followed by autologous hematopoietic stem cell rescue. Stage II/III patients received chest wall radiation and tamoxifen (if hormone-receptor positive) after CTM. The 5-year event-free survival (EFS) for stage II/IIIA patients with 10 or more involved axillary lymph nodes (n = 80) was 62 +/- 12%. Hormone receptor-positive patients with 10 or more nodes did significantly better than negative patients. The EFS for stage IIIB patients at 5 years was 44 +/- 19%; for stage IV patients at 5 years was 17 +/- 10%. Stage IV patients achieving complete response in viscera and/or soft tissue prior to CTM did significantly better than those achieving a partial response. There were six (3%) treatment-related deaths including two due to diffuse alveolar hemorrhage. There were no episodes of delayed interstitial pneumonitis. There were six severe cardiac events in 91 patients (6.6%) but none after instituting mitoxantrone dose-adjustment in the final 100 patients. We conclude that CTM is associated with a low treatment-related mortality and little pulmonary toxicity. CTM produces excellent outcomes in stage II/IIIA patients with 10 or more involved axillary lymph nodes.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/pathology , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Disease-Free Survival , Dose-Response Relationship, Drug , Female , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Middle Aged , Mitoxantrone/administration & dosage , Mitoxantrone/adverse effects , Neoplasm Staging , Receptors, Estrogen/physiology , Receptors, Progesterone/physiology , Survival Analysis , Thiotepa/administration & dosage , Thiotepa/adverse effects , Treatment OutcomeABSTRACT
We studied the feasibility, toxicity, and efficacy of a 2-step approach to autologous stem cell transplantation for patients with acute myeloid leukemia in first remission. Step 1 consisted of consolidation chemotherapy including cytarabine 2000 mg/m2 twice daily for 4 days concurrent with etoposide 40 mg/kg by continuous infusion over 4 days. During the recovery from this chemotherapy, peripheral blood stem cells were collected under granulocyte colony-stimulating factor stimulation. Step 2, autologous stem cell transplantation, involved the preparative regimen of busulfan 16 mg/kg followed by etoposide 60 mg/kg and reinfusion of unpurged peripheral blood stem cells. A total of 128 patients were treated. During step 1, there was 1 treatment-related death. A median CD34+ cell dose of 14 (x10(6)/kg) was collected in 3 aphereses. Ten patients suffered relapse before transplantation, and 117 patients (91%) proceeded to transplantation. During step 2, there were 2 treatment-related deaths, and 35 patients subsequently suffered relapse. With median follow-up of 30 months, 5-year disease-free survival for all patients entered in the study is projected to be 55%. By cytogenetic risk group, 5-year disease-free survival is 73% for favorable-risk patients, 51% for intermediate-risk patients, and 0% for poor-risk patients. We conclude that this 2-step approach to autologous transplantation produces excellent stem cell yields and allows a high percentage of patients to receive the intended therapy. Preliminary efficacy analysis is very encouraging, with outcomes that appear superior to those of conventional chemotherapy.
Subject(s)
Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid/therapy , Acute Disease , Adolescent , Adult , Aged , Antigens, CD34/blood , Antineoplastic Combined Chemotherapy Protocols/blood , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/toxicity , Busulfan/administration & dosage , Cytapheresis , Cytarabine/administration & dosage , Cytogenetics , Disease-Free Survival , Etoposide/administration & dosage , Graft Survival , Hematopoietic Stem Cell Mobilization , Humans , Leukocyte Count , Middle Aged , Recurrence , Survival Rate , Transplantation, AutologousABSTRACT
BACKGROUND: It is uncertain which people with chronic myelogenous leukemia (CML) in chronic phase should receive conventional treatment (interferon and/or chemotherapy) versus high-dose therapy and a bone marrow transplant. There are no randomized trials comparing these approaches and analyses of data from non-randomized studies are complex, contradictory without sufficient detail to allow subject-level treatment decisions. OBJECTIVE: Determine appropriateness of high-dose therapy and bone marrow transplants in persons with CML in chronic phase with specific features. Develop a treatment algorithm. PANELISTS: nine leukemia experts from diverse geographic sites and practice settings. EVIDENCE: Boolean MEDLINE searches of chronic myelogenous leukemia and chemotherapy and/or transplants. CONSENSUS PROCESS: We used a modified Delphi-panel group judgment process. Age, prognostic score, disease duration, and type of conventional therapy and response were permuted to define 90 clinical settings. Each panelist rated appropriateness of high-dose therapy and a transplant versus conventional therapy on a 9-point ordinal scale (1, most inappropriate, 9, most appropriate) considering three types of donors: (1) HLA-identical siblings; (2) alternative donors (HLA-matched related or unrelated people other than an HLA-identical sibling); and (3) autotransplants. An appropriateness index was developed based on median rating and amount of disagreement. Relationship of appropriateness indices to permuted clinical variables was considered by analysis of variance and recursive partitioning. Preference between donor types was analyzed by comparing mean appropriateness indices of similar settings and a treatment algorithm developed. CONCLUSIONS: In people with CML in chronic phase and an HLA-identical sibling donor and in those with an alternative donor (but no HLA-identical sibling), a transplant was rated appropriate in those with a < or = partial cytogenetic response to interferon and uncertain or inappropriate in all other settings. Autotransplants were rated uncertain or inappropriate in all settings. Most of the variance in appropriateness ratings between different clinical settings was accounted for by response to interferon: complete versus < or = partial response. An HLA-identical sibling donor, when available, was always preferred to an alternative donor or autotransplant. In people without an HLA-identical sibling, an alternative donor was favored over an autotransplant at higher appropriateness indices and the converse at lower appropriateness indices.
Subject(s)
Algorithms , Antineoplastic Agents/therapeutic use , Bone Marrow Transplantation , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Adolescent , Adult , Combined Modality Therapy , Delphi Technique , Dose-Response Relationship, Drug , Histocompatibility Testing , Humans , Middle Aged , Prognosis , Tissue DonorsABSTRACT
BACKGROUND: Despite considerable data, there is still controversy over which adults with acute myelogenous leukemia (AML) in 1st remission should receive high-dose therapy and a bone marrow transplant rather than conventional-dose chemotherapy. Analyses of data from randomized trials are complex, conclusions sometimes contradictory and results not sufficiently detailed to allow subject-level decisions. OBJECTIVE: To determine appropriate use of high-dose therapy and bone marrow transplants in persons with AML in 1st remission with specific features. Develop a treatment algorithm. PANELISTS: Nine leukemia experts from diverse geographic sites and practice settings. EVIDENCE: Boolean MEDLINE searches of acute myelogenous leukemia and chemotherapy and/or transplants. CONSENSUS PROCESS: We used a modified Delphi-panel group judgment process. Age, WBC, cytogenetics and FAB-type were permuted to define 72 clinical settings. Each panelist rated appropriateness of high-dose therapy and a transplant versus conventional-dose chemotherapy on a nine-point ordinal scale (1, most inappropriate, 9, most appropriate) considering 3 types of donors: (1) HLA-identical siblings; (2) alternative donors (HLA-matched related or unrelated people other than an HLA-identical sibling); and (3) autotransplants. An appropriateness index was developed based on median rating and amount of disagreement. The relationship of appropriateness indices to the permuted clinical variables was considered by analysis of variance and recursive partitioning. Preference between donor types was analyzed by comparing mean appropriateness indices of comparable settings and a treatment algorithm developed. CONCLUSIONS: In people with an HLA-identical sibling, this type of transplant was rated appropriate in those with unfavorable cytogenetics and uncertain in all other settings. In people without an HLA-identical sibling, an alternative donor transplant was rated appropriate in those < 30 years with unfavorable cytogenetics, uncertain in those > 30 years and unfavorable cytogenetics and inappropriate in all other settings. Autotransplants were rated appropriate in people with unfavorable cytogenetics and uncertain in all other settings. An HLA-identical sibling donor, when available, was always preferred to an alternative donor transplant or autotransplant. In people without an HLA-identical sibling, an autotransplant was almost always favored over an alternative donor transplant with the magnitude of preference inversely correlated with transplant appropriateness.
Subject(s)
Antineoplastic Agents/therapeutic use , Bone Marrow Transplantation , Evidence-Based Medicine , Leukemia, Myeloid, Acute/therapy , Adult , Antineoplastic Agents/administration & dosage , Combined Modality Therapy , Dose-Response Relationship, Drug , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Transplantation, AutologousABSTRACT
We studied the use of autologous bone marrow transplantation (ABMT) as treatment for acute myeloid leukemia (AML) in adults up to age 60. We used a preparative regimen of busulfan 16 mg/kg plus etoposide 60 mg/kg and bone marrow purged with 100 microg/ml of 4-hydroperoxycyclophosphamide (4HC). We treated 50 first remission patients; there were two treatment-related deaths and 13 relapses. With median follow-up of 6.8 years (minimum 4.5) disease-free survival (DFS) is 70%, relapse rate 27% and overall survival 72%. Patients with favorable cytogenetics had DFS 78% and relapse 18% whereas unfavorable patients had DFS 63% and relapse rate 35%. For 25 patients in second or third remission there were five treatment-related deaths and seven relapses. DFS is 52% and relapse rate 35%. None of six patients with primary refractory AML had long-term disease control. These data support the use of ABMT with an intensive preparative regimen and purged bone marrow as a highly effective treatment for adults with AML.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bone Marrow Purging , Bone Marrow Transplantation , Cyclophosphamide/analogs & derivatives , Leukemia, Myeloid/therapy , Acute Disease , Adolescent , Adult , Busulfan/administration & dosage , Cyclophosphamide/administration & dosage , Disease-Free Survival , Etoposide/administration & dosage , Follow-Up Studies , Humans , Immunosuppressive Agents/administration & dosage , Leukemia, Myeloid/mortality , Leukemia, Myeloid/physiopathology , Middle Aged , Transplantation, AutologousABSTRACT
BACKGROUND: There is controversy over whether high-dose therapy and a bone marrow transplant is better than conventional-dose chemotherapy in adults with acute lymphoblastic leukemia (ALL) in first remission. This decision may depend on which type of donor is available: an HLA-identical sibling, an alternative donor transplant (HLA-matched related or unrelated people other than HLA-identical siblings), or autotransplant. OBJECTIVE: To determine the appropriate use of high-dose therapy and bone marrow transplants in ALL in first remission. Develop a treatment algorithm. PANELISTS: Nine leukemia experts from diverse geographic sites and practice settings. EVIDENCE: Boolean MEDLINE searches of acute lymphoblastic leukemia and chemotherapy and/or transplants. CONSENSUS PROCESS: We used a modified Delphi-panel group judgment process. Age, white blood cell (WBC) count, cytogenetics and immune type were permuted to define 48 clinical settings. Each panelist rated appropriateness of high-dose therapy and a transplant versus conventional-dose chemotherapy on a 9-point ordinal scale (1, most inappropriate; 9, most appropriate) considering three types of donors: (1) HLA-identical siblings; (2) alternative donors; and (3) autotransplants. An appropriateness index was developed based on median rating and amount of disagreement. Relationship of appropriateness indices to the permuted clinical variables was considered by analysis of variance and recursive partitioning. Preference between donor types was analyzed by comparing mean appropriateness indices of comparable settings and a treatment algorithm was developed. CONCLUSIONS: In people with an HLA-identical sibling donor, transplants were rated appropriate in those with unfavorable cytogenetics and uncertain in all other settings. An HLA-identical sibling donor was always preferred to an alternative donor or autotransplant. In people without an HLA-identical sibling but with an alternative donor, this type of transplant was rated appropriate in those with unfavorable cytogenetics. However, an autotransplant was preferred over an alternative donor transplant in all other settings where a transplant was rated uncertain. In people without an HLA-identical sibling or alternative donor, autotransplants were rated uncertain in all settings except in those with not unfavorable cytogenetics, WBC < 100 x 10(9) l(-1) and T- or pre-B-cell type where they were rated inappropriate.
Subject(s)
Antineoplastic Agents/administration & dosage , Bone Marrow Transplantation , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Adolescent , Adult , Bone Marrow Transplantation/standards , Combined Modality Therapy , Delphi Technique , Evaluation Studies as Topic , Histocompatibility Testing , Humans , Leukocyte Count , Middle Aged , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology , Remission Induction , Tissue Donors , Transplantation, AutologousABSTRACT
Recombinant human granulocyte colony-stimulating factor (G-CSF; filgrastim) shortens the time to neutrophil recovery after intensive chemotherapy, but its role in the treatment of adults with acute lymphoblastic leukemia (ALL) is uncertain. We randomly assigned 198 adults with untreated ALL (median age, 35 years; range, 16 to 83) to receive either placebo or G-CSF (5 microgram/kg/d) subcutaneously, beginning 4 days after starting intensive remission induction chemotherapy and continuing until the neutrophil count was >/=1, 000/microL for 2 days. The study assignment was unblinded as individual patients achieved a complete remission (CR). Patients initially assigned to G-CSF then continued to receive G-CSF through 2 monthly courses of consolidation therapy. Patients assigned to placebo received no further study drug. The median time to recover neutrophils >/=1,000/microL during the remission induction course was 16 days (interquartile range [IQR], 15 to 18 days) for the patients assigned to receive G-CSF and 22 days (IQR, 19 to 29 days) for the patients assigned to placebo (P < .001). Patients in the G-CSF group had significantly shorter durations of neutropenia (<1, 000/microL) and thrombocytopenia (<50,000/microL) and fewer days in the hospital (median, 22 days v 28 days; P = .02) compared with patients receiving placebo. The patients assigned to receive G-CSF had a higher CR rate and fewer deaths during remission induction than did those receiving placebo (P = .04 by the chi-square test for trend). During Courses IIA and IIB of consolidation treatment, patients in the G-CSF group had significantly more rapid recovery of neutrophils >/=1,000/microL than did the control group by approximately 6 to 9 days. However, the patients in the G-CSF group did not complete the planned first 3 months of chemotherapy any more rapidly than did the patients in the placebo group. Overall toxicity was not lessened by the use of G-CSF. After a median follow-up of 4. 7 years, there were no significant differences in either the disease-free survival (P = .53) or the overall survival (P = .25) for the patients assigned to G-CSF (medians, 2.3 years and 2.4 years, respectively) compared with those assigned to placebo (medians, 1.7 and 1.8 years, respectively). Adults who received intensive chemotherapy for ALL benefited from G-CSF treatment, but its use did not markedly affect the ultimate outcome.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Granulocyte Colony-Stimulating Factor/therapeutic use , Neutropenia/prevention & control , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Remission Induction , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Double-Blind Method , Filgrastim , Humans , Length of Stay , Middle Aged , Neutropenia/chemically induced , Placebos , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Recombinant Proteins , Survival Rate , Thrombocytopenia/chemically induced , Thrombocytopenia/prevention & controlABSTRACT
Modern intensive chemotherapy programs have identified several important prognostic factors for treatment outcomes in adult acute lymphoblastic leukemia. This has allowed clinicians to tailor treatment regimens designed specifically for the various patient subgroups. Of adult ALL patients, 75% have B-lineage disease, and certain biologic characteristics in these patients, including older age and the incidence of mediastinal and CNS disease, differentiate them from T-cell patients. Most of the high-risk cytogenetics are found in the B-lineage group, making cytogenetics the single most powerful prognostic factor in ALL after failure to respond to initial treatment. Currently, there is no subgroup of ALL patients in which standard chemotherapy can be described as adequate, and improved treatment is needed for all groups of patients. These improvements will come from prospective randomized trials. At this time, allogeneic transplant remains the treatment of choice for high-risk ALL.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Adult , Burkitt Lymphoma/drug therapy , Humans , Leukemia-Lymphoma, Adult T-Cell/drug therapy , Leukocyte Count , Middle Aged , Precursor Cell Lymphoblastic Leukemia-Lymphoma/classification , Prognosis , Randomized Controlled Trials as Topic , Remission Induction , Risk AssessmentABSTRACT
PURPOSE: To determine the impact of high-dose cytarabine (ARA-C) (HDAC) dose modification, based on renal function, on the incidence of neurotoxicity (NT). PATIENTS AND METHODS: We retrospectively analyzed the records of 256 patients treated with HDAC (> or = 2.0 g/m2 per dose) for acute myelogenous leukemia (AML) at the University of California, San Francisco (UCSF). From 1985 to 1994, a total of 358 cycles of HDAC were administered, using either a twice-daily schedule (n = 208) or a once-daily regimen (n = 48). In 1989, a dose-modification algorithm was initiated at our institution, which reduced ARA-C doses in the setting of renal insufficiency (RI). For patients with a serum creatinine (Cr) level of 1.5 to 1.9 mg/dL during treatment, or an increase in Cr during treatment (deltaCr) of 0.5 to 1.2 mg/dL, ARA-C was decreased to 1 g/m2 per dose. For patients with a Cr > or = 2.0 mg/dL or a deltaCr greater 1.2 mg/dL, the dose was reduced to 0.1 g/m2/d. RESULTS: Overall, the incidence of NT was 16% (34 of 208) for patients treated with twice-daily HDAC and 0% (none of 48) for patients treated with daily HDAC (P = .003). NT occurred more often in patients treated on a twice-daily schedule with 3 g/m2 per dose compared with 2 g/m2 per dose (25% v 8%; P = .009). NT occurred in 55% of the twice-daily-treated patients with RI, compared with 7% of those with normal renal function (P = .00001). In patients with RI, NT occurred in none of 11 dose-modified cycles versus five of 11 (45%) total unmodified cycles (P = .01). None of 14 patients treated with once-daily HDAC given during RI developed NT, compared to 55% of patients (23 of 42) receiving twice-daily HDAC during RI (P = .009). By univariate analysis, NT was not associated with patient age or serum alkaline phosphatase, but NT was significantly increased in patients treated with twice-daily HDAC when the serum bilirubin was > or = 2.0 mg/dL compared with twice-daily HDAC given when the total bilirubin was less than 2.0 mg/dL (33% v 14%; P = .017). Multivariate analysis confirmed that RI was the most significant risk factor associated with the development of NT. CONCLUSION: HDAC NT is strongly associated with RI. The risk of HDAC NT can be reduced by the following: (1) routinely reducing the ARA-C dose from 3 to 2 g/m2 per dose; (2) modifying the ARA-C dose based on daily Cr values; and (3) administering HDAC on a once-daily rather than twice-daily schedule.
Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Cytarabine/administration & dosage , Neoplasms/complications , Nervous System Diseases/prevention & control , Renal Insufficiency/complications , Adult , Antimetabolites, Antineoplastic/adverse effects , Cytarabine/adverse effects , Drug Administration Schedule , Female , Humans , Incidence , Male , Middle Aged , Neoplasms/drug therapy , Nervous System Diseases/chemically induced , Renal Insufficiency/physiopathology , Retrospective Studies , Risk FactorsABSTRACT
BACKGROUND AND STUDY AIMS: Previous reports have suggested that endoscopic evaluation, with histological and microbiological examination of biopsied tissue, is required to diagnose gastrointestinal disease accurately in patients after allogeneic bone-marrow transplantation. We sought to further define the usefulness, yield, and sensitivity of endoscopic tissue biopsy in this patient population. PATIENTS AND METHODS: A retrospective review of the clinical, endoscopic, histological, and microbiological data was obtained during the evaluation and treatment of 61 distinct episodes of unexplained gastrointestinal complaints in 37 adult allogeneic bone-marrow transplant recipients over six years at our institution. RESULTS: Acute gastrointestinal graft-versus-host disease was found in 12 of the 61 episodes (20%). Gastrointestinal infections were found in 14 of the 61 episodes (23%); there were Herpesvirus infections (n = 8) and fungal infections (n = 9). Patients with and without graft-versus-host disease were similar in terms of their age, sex, underlying illness, clinical symptoms and signs, physical examination, laboratory values, and endoscopic findings. Small-bowel biopsy had a sensitivity of 90% for detecting the pathological changes of acute intestinal graft-versus-host disease in this series. CONCLUSION: A high percentage of patients with gastrointestinal complaints after allogeneic bone-marrow transplantation have acute gastrointestinal graft-versus-host disease, or an opportunistic infection. Gastrointestinal graft-versus-host disease cannot be accurately diagnosed from its clinical presentation. Endoscopic small-bowel biopsy is an essential tool in evaluating this patient population.
Subject(s)
Bone Marrow Transplantation/adverse effects , Gastrointestinal Diseases/diagnosis , Graft vs Host Disease/diagnosis , Acute Disease , Adult , Biopsy , Case-Control Studies , Endoscopy, Gastrointestinal , Female , Humans , Male , Opportunistic Infections/diagnosis , Retrospective Studies , Sensitivity and SpecificityABSTRACT
A syndrome indistinguishable from idiopathic polymyositis occurred in 11 patients as a manifestation of chronic GVHD. All patients had elevation of creatine phosphokinase (CPK). Immunohistology demonstrated the effector cells in the muscle infiltrates as cytotoxic T cells, a finding similar to idiopathic polymyositis. Polymyositis is a rarely reported complication of chronic graft-versus-host disease (GVHD) with only 8 cases described in the literature. We encountered this syndrome in a small but significant percentage of our patients with chronic GVHD. Polymyositis associated with chronic GVHD does not affect the overall prognosis for the patient. Moreover, polymyositis can be the only manifestation of chronic GVHD. Awareness of this complication is important because it can be confused with other causes of muscle weakness after bone marrow transplantation. Finally, prompt initiation of corticosteroid therapy results in a rapid improvement of the associated symptoms.
Subject(s)
Bone Marrow Transplantation/adverse effects , Graft vs Host Disease/diagnosis , Polymyositis/diagnosis , Adolescent , Adult , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/therapeutic use , Antibodies, Monoclonal , Child , Child, Preschool , Chronic Disease , Diagnosis, Differential , Female , Graft vs Host Disease/drug therapy , Graft vs Host Disease/etiology , Humans , Infant , Male , Middle Aged , Prednisone/administration & dosage , Prednisone/therapeutic use , Retrospective StudiesABSTRACT
We have previously documented that adults with de novo acute myelogenous leukemia (AML) who are induced into first complete remission with mitoxantrone and high-dose cytarabine are more likely than those induced with daunorubicin and high-dose cytarabine to develop a bone marrow injury pattern with delayed cytopenias after achieving initial complete remission, a phenomenon we have termed post-remission cytopenia syndrome. We therefore retrospectively compared the engraftment kinetics of mitoxantrone and daunorubicin patients following 4-hydroperoxycyclophosphamide (4HC) purged autologous bone marrow transplant (ABMT) with busulfan-etoposide conditioning. Despite equivalent graft colony forming units granulocyte macrophage (CFU-GM), mitoxantrone patients (n = 13) took a median 7 weeks longer to achieve 1.0 x 10(9)/l granulocytes, 5 weeks longer to achieve platelet transfusion independence, and 10 weeks longer to achieve red blood cell transfusion independence, and required more platelet transfusions (P = 0.008), than daunorubicin patients (n = 13). Patients experiencing the post-remission cytopenia syndrome (n = 11) had significantly slower engraftment than those not experiencing the syndrome (n = 15; P < or = 0.04). Two mitoxantrone and five daunorubicin patients have relapsed after ABMT (P = 0.38). We conclude that the type of induction chemotherapy used in untreated adults with de novo AML can influence subsequent engraftment after 4HC-purged ABMT. We believe that mitoxantrone combined with high-dose cytarabine should be avoided as induction chemotherapy in patients for whom 4HC-purged ABMT is planned.
Subject(s)
Antineoplastic Agents/therapeutic use , Bone Marrow Purging , Bone Marrow Transplantation , Cyclophosphamide/analogs & derivatives , Leukemia, Myeloid, Acute/therapy , Mitoxantrone/therapeutic use , Adult , Cyclophosphamide/pharmacology , Female , Humans , Male , Middle Aged , Mitoxantrone/adverse effects , Transplantation, AutologousABSTRACT
A patient underwent an HLA-identical ABO-compatible allogeneic bone marrow transplant for aplastic anemia. She then developed pure red cell aplasia which was treated successfully with antithymocyte globulin and methylprednisolone, after failing to respond to intravenous immune globulin infusion.
Subject(s)
Anemia, Aplastic/surgery , Bone Marrow Transplantation/adverse effects , Glucocorticoids/therapeutic use , Immunoglobulins, Intravenous/therapeutic use , Methylprednisolone/therapeutic use , Red-Cell Aplasia, Pure/therapy , ABO Blood-Group System/immunology , Adult , Anemia, Aplastic/immunology , Female , Histocompatibility Testing , Humans , Red-Cell Aplasia, Pure/etiology , T-Lymphocytes/immunology , Transplantation, HomologousABSTRACT
Various immune globulin products have been utilized in allogeneic bone marrow transplant (BMT) in an effort to decrease the incidence of cytomegalovirus (CMV) infection, infection due to other pathogens and graft versus host disease (GVHD). Controlled trials regarding the use of prophylactic immune globulin have been reviewed. Differences among products and use of various dosing regimens complicates the comparison of the results of one trial to another. Risk factors, such as donor and recipient CMV serology, GVHD prophylaxis, the use of white blood cell transfusions and conditioning regimens, vary significantly, further complicating the analysis. Autologous BMT patients do not appear to benefit from prophylactic globulin therapy. The effectiveness of immune globulin in the prevention of CMV disease in allogeneic BMT is questionable; other measures, including prophylactic ganciclovir and screening of blood products appear to be of greater value. Immune globulin inconsistently decreases the incidence of infection due to pathogens other than CMV. The best established role for prophylactic immune globulin in allogeneic BMT is in the prevention of GVHD.