Autologous bone marrow transplantation in patients with non-Hodgkin's lymphoma: comparison of different parameters in predicting the kinetics of haematological recovery

We analysed the kinetics of haematological recovery after autologous bone marrow transplantation (ABMT) in 31 patients with non-Hodgkin's lymphoma, of whom 14 had received chemotherapy and 17 had received no chemotherapy before marrow harvesting. The time for recovery of polymorph (PMN) and platelet numbers was assessed in relation to patient's sex, age, the numbers of mononuclear cells (MNC) and of granulocyte-macrophage colony-forming cells (CFU-GM) reinfused, the therapy before harvesting and the conditioning regimens. The results showed that the most important factor influencing the speed of haematological recovery was therapy before marrow collection; recovery was faster in patients not treated before harvesting than in those treated. The mean day for PMN recovery to 0.5 x 10(9)/l was 14.6 vs 21.8 (p less than 0.001); the mean day for platelet recovery to 50 x 10(9)/l was 16.5 vs 44.4 (p less than 0.00002). The other parameters assessed did not correlate with the kinetics of haemopoietic recovery. We conclude that NHL patients who undergo ABMT without chemotherapy prior to marrow harvest have rapid haematological recovery, which suggests that better timing of the harvest could be of value in the management of NHL patients for whom 'reinforcement' with ABMT is scheduled.     

T-cell-depleted autologous bone marrow transplantation therapy: analysis of immune deficiency and late complications

Fourteen patients with T-cell-derived leukemia and lymphoma underwent high-dose chemoradiotherapy and anti-T-cell monoclonal antibody-treated autologous bone marrow transplantation (ABMT). All patients were either in sensitive relapse or had adverse prognostic features, and five patients had a history of bone marrow involvement with disease. Patients received a median of 2 (1 to 3) prior chemotherapy regimens; 10 patients received local radiotherapy. After high-dose ablative therapy, greater than 500/mm3 granulocytes and greater than 20,000 untransfused platelets/mm3 were noted at a median of 23 (13 to 48) and 26 (15 to 43) days post-ABMT, respectively. Natural killer (NK) cells, T cells (predominantly T8+), and monocytes were noted within the first 1 to 2 months post-AMBT, as seen in other series. Disease-free survival was a median of 10.1 months, 5.9 months for patients with T acute lymphoblastic leukemia or lymphoblastic lymphoma and 25.6 months for patients with T non-Hodgkin's lymphoma (NHL). Toxicities were common and severe. Thirty-six percent of patients developed bacteremias early post-BMT. Late complications included a skin rash consistent with graft versus host disease; infections with Herpes zoster, hepatitis, and Pneumocystis carinii; and the development of Epstein-Barr virus associated lymphoproliferative syndrome. Our findings suggest that patients who have undergone T-depleted ABMT have a profound immunodeficiency not reflected in the phenotypic reconstitution of the T and NK cells. Characterization of the functional deficiency may facilitate the development of methods to reduce the long-term toxicity of AMBT in these patients.     

Autologous peripheral blood stem cell transplantation after high dose therapy in patients with advanced lymphomas.

Thirty-eight patients with refractory or relapsed non-Hodgkin's lymphoma (19 patients) or Hodgkin's disease (19 patients) were treated with salvage therapy. The peripheral stem cell collection was performed during hematologic recovery after myeloablative chemotherapy. In eight patients with Hodgkin's disease the number of CFU-GM collected was less than 0.5 x 10(4)/kg and these patients were excluded for stem cell transplantation. In the remaining 30 patients, a median of 4 x 10(4) CFU-GM/kg was collected (range 0.8-100 x 10(4)/kg) by three leukaphereses in 25 patients and six to 11 leukaphereses in five patients. Conditioning regimens were CBV (eight), BEAM (six), BEAC (10) and cyclophosphamide + total body irradiation (TBI) (six). Without TBI, the mean time for reaching a granulocyte count greater than 0.5 x 10(9)/l was 18 days and for a platelet count greater than 50 x 10(9)/l was 19 days in 23 out of 24 patients. With TBI, in five patients the mean time for reaching a granulocyte count greater tahn 0.5 x 10(9)/l was 37 days and for a platelet count greater than 50 x 10(9)/l was greater than 100 days. Complications were minor. There was only one toxic death. The outcome in these patients was similar to that observed in patients who received autologous bone marrow transplantation for advanced lymphomas. In conclusion, we observed good hematologic recovery except when TBI was used in the conditioning regimen.     

Studies of oral neutrophil levels in patients receiving G-CSF after autologous marrow transplantation

Patients are at risk of mucositis and infections in the oral cavity during the neutropenic period after chemotherapy, which are significant causes of morbidity. In phase I/II studies with the haemopoietic growth factor granulocyte colony stimulating factor (G-CSF), a reduction in post-chemotherapy mucositis has been observed in addition to haematologic effects. To understand this phenomenon better in patients receiving G-CSF following high-dose chemotherapy with autologous bone marrow transplantation (ABMT), we studied the effects of G-CSF on levels of neutrophils recoverable from the oral cavity using a quantitative mouthrinse assay. In normal subjects, mouthrinses contained 472 +/- 329 x 10(3) neutrophils/mouthrinse. After chemotherapy followed by ABMT, mouthrinse neutrophil levels decreased to undetectable levels during the neutropenic period, but recovered 1-2 and 3-9 d before circulating neutrophil levels reached 0.1 and 1 x 10(9)/l respectively, whether or not patients received G-CSF. In patients who received G-CSF, the mean cumulative mucositis score was reduced from 35 +/- 9 to 21 +/- 12 (P < 0.05), and the maximum mean daily mucositis score was reduced from 2.8 +/- 0.5 to 1.7 +/- 0.9 (P < 0.01), compared to patients who did not receive G-CSF after ABMT. These studies provide in vivo evidence that neutrophils produced during G-CSF therapy are available to leave the circulation and enter tissues where their function is required for host defence. Since the usual temporal relationship between oral and peripheral blood neutrophil recovery was preserved during G-CSF administration after ABMT, these data support the hypothesis that the reduction in post-ABMT mucositis observed with G-CSF therapy may reflect a beneficial effect of G-CSF on the kinetics of oral mucosal neutrophil recovery in addition to the effect of G-CSF to accelerate peripheral blood neutrophil recovery.     

Characteristics of engraftment after repeated autologous bone marrow transplantation

The rate of engraftment after autologous bone marrow transplantation (ABMT) is extremely variable and largely unpredictable. To identify factors influencing engraftment, we studied 35 patients with refractory germ cell tumors undergoing high-dose chemotherapy with carboplatin (900-2000 mg/m2) and etoposide (1200 mg/m2) with bone marrow rescue. Prior to the initiation of chemotherapy, bone marrow sufficient for two marrow infusions was harvested (range 0.86-4.82 x 10(8) nucleated cells per kg). All 35 patients received half of the collected bone marrow 3 days after the last dose of chemotherapy; 23 responders received a second round of the same chemotherapy followed by infusion of the second half of the bone marrow. Eighteen patients could be compared for the two transplant episodes. The "rate of engraftment" was defined as the unweighted mean of four parameters: 1) the number of days until the absolute granulocyte count surpassed 0.2 x 10(9)/liter, 2) the number of days until the absolute granulocyte count surpassed 0.5 x 10(9)/liter, 3) the number of days until the last platelet transfusion, and 4) the number of days until the reticulocyte count surpassed 25 x 10(9)/liter. No significant correlation was found between rate of engraftment and such factors as the number of nucleated cells per kg infused, the dose of chemotherapy, extent of prior chemotherapy, tumor response to the high-dose chemotherapy, age of the patient, or the days of granulocytopenic fever (all p greater than 0.20). In contrast, a close correlation was found for the number of units of platelets (p = 0.005) and red blood cells (p = 0.006) transfused following each of the two transplants. There was no significant difference between rate of engraftment after first and second transplantation. Comparison of these data with the results obtained in reported ABMT with separate harvests suggests that the characteristics of the infused marrow determine the rate of engraftment after ABMT. This model of repeated transplantation could provide an important tool for assessing the therapeutic efficacy of hematopoietic growth factors.     

Addition of peripheral blood stem cells collected without mobilization techniques to transplanted autologous bone marrow did not hasten marrow recovery following myeloablative therapy.

A randomized prospective trial was conducted to determine if the addition of cryopreserved autologous peripheral blood stem cells (PBSC) collected without mobilization techniques to autologous cryopreserved bone marrow for patients receiving an autologous bone marrow transplant (ABMT) affected the time to marrow function recovery. Thirty-five evaluable patients with various malignancies were studied. Sixteen received PBSC + ABMT and 19 received ABMT alone. The PBSC were collected with 4 h leukapheresis procedures on 3 consecutive days. No manipulations to increase the number of circulating stem cells were used during the collections. The median time to recover 0.5 x 10(9)/l circulating granulocytes was 20 days after transplantation in the ABMT group and 27 days in the PBSC + ABMT group (p = 0.12). The median time to recover 20 x 10(9)/l platelets was 22 days after transplantation in the ABMT group and more than 27 days in the PBSC + ABMT group (p = 0.29). The day of discharge from the hospital was earlier for the ABMT group (median 29 days) than the PBSC + ABMT group (median 35 days, p = 0.03). We did not find that the addition of non-mobilized PBSC to infused autologous marrow accelerates marrow recovery.     

High-dose therapy and autologous peripheral blood stem cell transplantation for patients with lymphoma

Forty patients with refractory Hodgkin's disease (24 patients) or non- Hodgkin's lymphoma (16 patients) who were considered for high-dose therapy but not for autologous bone marrow transplantation (ABMT) due to BM metastases, previous pelvic irradiation, a history of marrow involvement by tumor or hypocellular marrow in conventional harvest sites received high-dose therapy and autologous peripheral blood (PB) hematopoietic stem cell transplantation. Disappearance of circulating neutrophils and development of RBC and platelet transfusion-dependence was followed, in the evaluable patients, by reappearance of 0.5 x 10(9)/L circulating granulocytes and sufficient platelets to obviate the need for platelet transfusions at a median of 25 days after transplantation. Twenty-three patients experienced a clinical complete remission (CR). The projected 2-year event-free survival was 24% for all 40 patients and 49% for the non-Hodgkin's lymphoma patients. The projected 18-month event-free survival for the Hodgkin's disease patients was 15%. PB stem cell transplantation provided an opportunity to administer high-dose salvage therapy to patients with refractory lymphoma who otherwise were not candidates for such therapy. For some of those patients, the high-dose therapy produced prolonged survival, free of tumor progression.     

Monoclonal antibody purging and autologous bone marrow transplantation in acute myelogenous leukemia in complete remission

A mouse monoclonal antibody (S4-7) reacting with human myelomonocytic cells has been previously shown to be suitable for bone marrow purging in selected acute myelogenous leukemia (AML) patients with S4-7 positive leukemic clonogenic cells at diagnosis. The results obtained in seven AML patients who underwent such a treatment, followed by autologous bone marrow transplantation (ABMT), are now reported. Six patients underwent ABMT in first complete remission (CR), one in second CR, after BAVC conditioning regimen. One patient died of infection 1 month after ABMT; in the other six a complete recovery of hemopoiesis was observed. In spite of S4-7 reactivity with normal myelomonocytic cells, a prompt recovery of granulopoiesis was however observed both in in vitro liquid culture and in vivo with a median time of 20 days to reach granulocyte values of 500 x 10(6)/l. The patient transplanted in 2nd CR relapsed 3 months after ABMT. Of the five evaluable patients transplanted in 1st CR, two relapsed 8 and 9 months post-ABMT while three remain in continuous CR at 35, 47, 57 months. Leukemic cells of two of the three patients with recurrent disease were studied at relapse and in both could be detected a significant percentage of S4-7 negative cells, detectable neither at diagnosis nor (one patient) at the time of first relapse after standard chemotherapy.     

Supernatant cell counts from long-term bone marrow culture correlate with the speed of engraftment following autologous bone marrow transplantation.

This study evaluates the relationship between bone marrow growth in a long-term bone marrow culture (LTBMC) system and speed of engraftment of the same marrow following autologous bone marrow transplantation (ABMT). Bone marrow from 21 patients transplanted with unmanipulated, non-cryopreserved autologous marrow was cultured. Samples from 21 normal donors were cultured to establish the normal supernatant cell count range. Supernatant counts from LTBMCs established from marrow taken from patients at the time of bone marrow harvest were compared with the time to neutrophil and platelet engraftment. Supernatant counts, particularly after 1 week in culture, showed close correlation with time to neutrophil and platelet engraftment following ABMT (r = 0.733, p less than 0.01; r = 0.735, p less than 0.01 respectively). Where supernatant cell counts were within the normal range rapid engraftment was predicted (neutrophils greater than 0.5 x 10(9)/l within 21 days, platelets greater than 50 x 10(9)/l within 28 days) and if supernatant counts were below this range, engraftment was predicted to be delayed. After 1 week in culture, the speed of neutrophil and platelet engraftment were correctly predicted in 19 and 18 cases respectively. Preliminary data suggest that LTBMC of marrow obtained 2-6 weeks before harvesting provides similar data, thus allowing the opportunity to intervene, for example with growth factors, in selected patients.     

The effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) on platelet recovery in breast cancer patients undergoing autologous bone marrow transplantation

OBJECTIVE: To assess the safety and efficacy of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) administered after autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS: Two randomized, double-blind, placebo-controlled studies were done. In the phase 1/2 study, 75 breast cancer patients underwent a bone marrow harvest and myeloablative STAMP V chemotherapy and were randomized to receive placebo or one of three doses of PEG-rHuMGDF. In the phase 3 study, 64 patients were randomized to receive placebo or the minimally effective dose of PEG-rHuMGDF. The study drug was administered daily starting on the day of bone marrow infusion until the platelet count was greater than or equal to 50 x 10(9)/L (without transfusion) or for a maximum of 28 days. All patients received 10 microg/kg/day filgrastim starting on day 2 until neutrophil count recovery. RESULTS: PEG-rHuMGDF appeared to be safe and well tolerated. No significant differences were noted in mortality or disease progression rates. Antibodies to MGDF were not observed. In the phase 1/2 study, the time to platelet recovery to greater than or equal to 20 x 10(9)/L and platelet transfusion requirements were significantly reduced for patients treated with PEG-rHuMGDF compared with placebo (p < 0.05). In the phase 3 study, no significant differences in the kinetics of early thrombopoiesis or platelet transfusions after ABMT were observed. CONCLUSIONS: PEG-rHuMGDF was not consistently efficacious in reducing the duration of severe thrombocytopenia. The maximum platelet counts for PEG-rHuMGDF-treated patients occurred a median of 2 weeks after the last dose of drug, suggesting that the biologic effects of this hematopoietic cytokine are delayed compared with other hematopoietic cytokines.     

rIL2／LAK细胞净化的自体骨髓移植治疗白血病

用ｒＩＬ２和自体外周血克隆化ＬＡＫ细胞体外二步净化白血病髓后行ＡＢＭＴ，移植后体内再用ｒＩＬ２／ＬＡＫ细胞治疗；４例行ＡＢＭＴ白血病病人用ｒＩＬ２／ＬＡＫ细胞体内外净化后，２例对化疗无效的病人获ＣＲ，４例病人移植后至１９９４年９月持续缓解８－１４月，移植后第３周末测定外周血ＮＫ细胞活性明显高于另３例未净化行ＡＢＭＴ白血病病人；ｒＩＬ２／ＬＡＫ细胞体外二步净化骨髓不影响ＣＦＵ－ＧＭ回收率，移植后不曩     

The effect of macrophage colony-stimulating factor on haemopoietic recovery after autologous bone marrow transplantation

Macrophage colony-stimulating factor (M-CSF) is active in the late stages of monocyte maturation, activates mature monocyte-macrophages and enhances their production of various other cytokines. We have examined the effects of a 21 d course of escalating doses of M-CSF purified from human urine (hM-CSF) on recovery following autologous bone marrow transplantation (ABMT) in 20 patients with malignant lymphomas. Four patients were treated at each dose level of 4, 8, 16, 32 and 64 x 10(6) U/m2/d and results compared to 46 concurrent controls. There was no significant difference in recovery to an absolute neutrophil count (ANC) of 0.5 x 10(9)/l (median 20 d in hM-CSF group versus 22 in controls) or in recovery of platelets to 50 x 10(9)/l (32 d versus 39 d, 0.05 less than P less than 0.1); hM-CSF patients received a median of 81 platelet units following ABMT (controls 112 units, P = NS). hM-CSF patients had a median of 5.5 d with fever greater than 37.5 degrees C (control 8, P = NS), received parenteral antibiotics for 14.5 d (control 17, P = NS) and had a 50% incidence of bacteraemia (control 48%). hM-CSF treated patients were discharged by a median of day 29 following transplantation (control 33, P less than 0.05). Platelet and neutrophil recovery correlated significantly with the number of marrow mononuclear cells (MNC) reinfused in the hM-CSF group (P = 0.05 and P = 0.014 respectively) but not in controls. Subgroup analysis showed that hM-CSF patients receiving greater than 2 x 10(8) MNC/kg body weight reached an ANC of 0.5 x 10(9)/l by a median of day 16.5 (control 18.5, NS), became platelet transfusion independent by day 17 (control 29, P less than 0.05) and reached a platelet count of 50 x 10(9)/l by day 21 (control 40, P less than 0.05). No significant toxicity attributable to hM-CSF treatment was seen. These results suggest that hM-CSF accelerates platelet recovery following ABMT and that relatively large marrow innocula are required to see this effect.     

The place of high-dose BEAM therapy and autologous bone marrow transplantation in poor-risk Hodgkin's disease. A single-center eight- year study of 155 patients

Although high-dose chemotherapy and autologous bone marrow transplantation (ABMT) are increasingly being used for the treatment of relapsed and resistant Hodgkin's disease, there have been few large, single-center studies reported with adequate follow-up to allow full evaluation of this therapeutic modality. We present 155 poor-risk Hodgkin's disease patients who received high-dose BEAM (BCNU, etoposide, cytosine arabinoside, and melphalan) chemotherapy and ABMT who have been studied over a period of 8 years. All patients had either not attained a remission on mechlorethamine, vincristine, procarbazine, prednisone-type therapy and had poor prognostic features at presentation, not attained a complete remission or relapsed within 1 year of an initial alternating regimen, or not attained remission with two or more lines of treatment. At the time of ABMT the relapse status of the patients was as follows: 46 patients were primarily refractory to induction therapy, 7 were good partial responders, 52 were in first relapse, 37 in second relapse, and 13 in third relapse. Seventy-eight patients had chemoresistant disease, 33 had chemosensitive disease at the time of ABMT, and 44 were untested for chemosensitivity at latest relapse. The procedure related mortality in the first 90 days post-ABMT of 10% overall. At 3 months 43 patients (28%) were assessed as complete responders, 72 patients had a partial response (46%), and 24 patients (16%) had no response or progression of disease. However, by 6 months, 53 (24%) patients were assessed as complete responders and 51 (33%) patients had nonprogressive disease. Forty-five patients had received radiotherapy post-ABMT to residual masses (41 patients) or to previous sites of bulk disease (4 patients). The actuarial overall and progression-free survival at 5 years was 55% and 50%, respectively. On multivariate analysis patients with bulk (masses > 10 cm), heavily pretreated patients (those receiving three or more lines of treatment) and females had a significantly poorer prognosis. Relapse status was also significant for progression-free survival in that patients in second (60%) and third relapse (70%) had a better prognosis than those in first relapse (44%) or with primary refractory disease (33%). Response to prior chemotherapy did not predict for progression-free survival. These results enable comparisons to be made between high-dose chemotherapy with ABMT and conventional dose salvage therapy. Furthermore, although the results as a whole are highly encouraging, certain groups carry an unfavorable prognosis.     

Parma international protocol: pilot study of DHAP followed by involved-field radiotherapy and BEAC with autologous bone marrow transplantation

Fifty patients with intermediate- or high-grade non-Hodgkin's lymphoma (NHL) who had relapsed after a complete remission induced by an Adriamycin-containing chemotherapy regimen participated in this prospective pilot study. The patients ranged in age from 16 to 60 years (median 42 years). All patients received dexamethasone, high-dose cytarabine, and cisplatin (DHAP) for two courses at 3- to 4-week intervals. Patients achieving a partial or complete response were scheduled to receive involved-field radiotherapy and high-dose carmustine, etoposide, cytarabine, and cyclophosphamide (BEAC), followed by autologous bone marrow transplantation (ABMT). Among 48 evaluable patients (ie, 1 was lost to follow-up and 1 had no measurable disease) 7 patients obtained a complete response (CR) and another 21 patients achieved partial response (PR), whereas the remaining 20 patients failed. One responder died of treatment-related toxicity, and six others declined ABMT. The patient with no measurable disease did not progress on DHAP and was submitted to ABMT. Twenty-two patients underwent ABMT [20 with BEAC and 2 with cyclophosphamide plus total body irradiation (TBI)] of whom 2 (9%) died of toxicity and 10 relapsed. One patient was a suicide at 28 months post-ABMT in CCR and 9 are alive disease-free 24 months to 32 months (median 30 months) post-ABMT. The actuarial 2-year event-free survival for patients undergoing transplantation is 40%. This prospective multicenter trial documents the ability of DHAP followed by ABMT to produce durable complete remission in a significant proportion of patients with relapsed aggressive NHL. Forty-four percent of all patients with relapsed lymphoma who entered the study actually underwent ABMT and 20% of the total group are projected to be long-term disease-free survivors.     

Mini-BEAM followed by BEAM and ABMT for very poor risk Hodgkin''s disease

High dose chemotherapy and autologous bone marrow transplantation (ABMT) is an effective form of salvage therapy in patients with relapsed or resistant Hodgkin's disease. Patients with large tumour masses at the time of ABMT have a poorer prognosis and we have therefore administered intermediate dose BCNU, etoposide, cytarabine and melphalan (mini-BEAM) prior to high dose therapy with the same agents (BEAM) and ABMT in such patients. In addition we have used the same strategy in patients with bone marrow infiltration at the time of relapse in an attempt to clear the bone marrow for transplant. A total of 23 patients received mini-BEAM and 21 proceeded to BEAM and ABMT. Platelet engraftment was delayed compared to BEAM recipients who had not received mini-BEAM (P = 0.008) but there was only one procedure related death. Responses to BEAM and ABMT were not predicted by the response to mini-BEAM indicating a dose response effect at the upper end of the dose intensity spectrum. At 2 years, the overall survival and progression free survival are 61% and 46% respectively for this group of Hodgkin's patients with extremely poor prognosis.     

Autologous bone marrow transplantation for patients with acute myeloid leukaemia and acute lymphoblastic leukaemia--a comparison

Forty-two patients with acute leukaemia were treated with autologous bone marrow transplantation (ABMT) using a combination chemotherapy protocol for bone marrow ablation. The response to high-dose chemotherapy and ABMT and its associated morbidity and mortality have been compared in 24 patients with acute myeloid leukaemia (AML) and 18 patients with acute lymphoblastic leukaemia (ALL). In 16 patients with AML treated with ABMT during first complete remission (CR), ten patients (62.5%) remain in unmaintained remission; median follow up is 32 months. In eight patients with ALL treated in first CR, only one remains in remission 32 months post-ABMT, with three patients dying non-leukaemic deaths. Fourteen of 18 patients (AML and ALL) treated after first remission have died of recurrent leukaemia, two died non-leukaemic deaths and two remain well 31 and 55 months post-ABMT; both have ALL. The length of hospital stay and the amount of blood product support were similar in both groups. Haematological recovery post-ABMT was delayed in patients with AML compared to patients with ALL but this difference was not significant. Rapidly progressive lung infection was thought to be the cause of four early deaths (4/18) in patients with ALL but none in patients with AML. Severe gram-negative infections were significantly more common in patients with AML.     

Peripheral blood stem cell transplants for multiple myeloma: identification of favorable variables for rapid engraftment in 225 patients

Transfusion of autologous peripheral blood stem cells (PBSCs) of good quality ensures fast hematopoietic engraftment after myeloablative therapy with a decrease in procedure-related morbidity and mortality. We have analyzed variables influencing the kinetics of engraftment, and therefore reflecting the quality of PBSC collections, in 225 patients with newly diagnosed or refractory multiple myeloma (MM) who received an autotransplant in support of high dose melphalan (200 mg/m2); 132 of these patients also completed a second transplant. All PBSCs were collected before the first transplant after high-dose cyclophosphamide (6 g/m2) and hematopoietic growth factors, mainly granulocyte- macrophage colony-stimulating factor. PBSCs were administered either alone (91 patients) or with bone marrow (134 patients). A highly significant correlation was observed between the number of CD34+ cells per kilogram infused and prompt recovery of both granulocytes (P = .0001) and platelets (P = .0001). After correction for the proportion of patients with > or = 2 x 10(6)/kg CD34 PBSCs infused and with < or = 12 months of prior therapy, no difference in engraftment kinetics was seen between patients receiving PBSCs only and those also receiving bone marrow. Exposure to chemotherapy, even to < or = 6 months of alkylating agents, significantly delayed hematopoietic recovery posttransplantation. The threshold dose of CD34 cells necessary for prompt engraftment was > or = 2.0 x 10(6)/kg for patients with < or = 24 months of chemotherapy before the first transplant, whereas greater than 5 x 10(6)/kg CD34 cells were required to assure rapid recovery also in those with longer exposure. Such quantities, easily collected in the large majority of patients with shorter exposure (91%), were obtained in only 28% of patients with more than 24 months of prior chemotherapy. Rapid platelet recovery within a narrow range of time (before day 14) was almost invariably seen (94%) when greater than 5 x 10(6)/kg CD34 cells were infused, irrespective of the duration of prior therapy, whereas the range widened progressively when less CD34 cells were infused. In the absence of CD34 measurements, fast recovery of platelets to greater than 50 x 10(9)/L within 14 days after high-dose cyclophosphamide and < or = 12 months of prior chemotherapy were the best predictors of early engraftment. Prudent use of stem cell-damaging agents, such as melphalan and nitrosoureas, is recommended in MM patients who might be candidates for autotransplantation. Alternatively, PBSCs should be collected early after diagnosis.     

'Relative' chemotherapy sensitivity: the impact of number of salvage regimens prior to autologous stem cell transplant for relapsed and refractory aggressive non-Hodgkin's lymphoma

The purpose of the study was to assess the impact of number of salvage regimens needed to demonstrate chemotherapy sensitivity on relapse rates, survival, and toxicity following high-dose therapy and autologous bone marrow transplantation (ABMT) in relapsed or refractory non-Hodgkin's lymphoma. We retrospectively reviewed 136 patients with intermediate-grade lymphoma who underwent ABMT. All patients were treated with salvage therapy to maximum tumor reduction. Three quarters (102/136) of the patients received one salvage regimen, while 31 (23%) patients received two or more regimens. When compared to patients requiring >or= two regimens, patients requiring only one salvage regimen to demonstrate chemosensitivity were more likely to have a longer previous CR from initial therapy (CR >or=12 months in 47% vs 26%; P = 0.04) and to have attained CR with salvage (54% vs 16%; P = 0.001). Both median relapse-free survival (RFS) and overall survival (OS) have not yet been reached in patients receiving one salvage regimen (median follow-up 50.6 months). This is superior to the median RFS of 9.1 months (P = 0.004) and OS of 11.1 months in patients requiring >or=two regimens to demonstrate chemosensitivity (P = 0.002). Time to engraftment, toxic deaths and incidence of myelodysplasia were similar in the groups. The survival rate observed in patients requiring >or=two salvage regimens, although inferior to that of patients receiving a single salvage regimen, are still generally superior to results in the literature for patients treated with chemotherapy alone without ABMT. We conclude that high-dose therapy with ABMT is appropriate for lymphoma patients even when disease reduction requires repeated numbers of salvage regimens.     

Difference in kinetics of hematopoietic reconstitution between ALL and ANLL after autologous bone marrow transplantation with marrow treated in vitro with mafosfamide (ASTA Z 7557)

The kinetics of hematopoietic recovery after autologous bone marrow transplantation (ABMT) reflect the hematopoietic capacity of the infused marrow. In vitro treatment of marrow with high doses of mafosfamide (ASTA Z 7557) alters the hematopoietic regenerative capacity of the graft. Thirty-two patients with acute leukemia (12 acute lymphoblastic leukemia (ALL) and 20 acute non-lymphoblastic leukemia (ANLL] with 27 in complete remission and five in partial remission were consolidated with cyclophosphamide (60 mg/kg x 2) and total body irradiation (10 Gy), followed by reinfusion of autologous marrow treated in vitro with mafosfamide. The marrow of each patient had been incubated with the highest tolerable dose of mafosfamide, individually predetermined from a preincubation test. We report here that the kinetics of engraftment are strikingly different in ANLL and ALL patients. In the ANLL group recovery to 0.1% reticulocytes took a median of 20.5 days (range 14-32) versus 15 (11-28) in the ALL group; 33.5 days (18-45) versus 19 (15-30) for leukocytes to reach 1.0 x 10(9)/l; 35 (19-60) versus 20.5 (15-30) for neutrophils to reach 0.5 x 10(9)/l; 110+ (45-480+) versus 50 (23-90) for platelets to reach 50 x 10(9)/l (p less than 0.01 and p less than 0.05). Detection of granulocyte-macrophage progenitors (CFU-GM) regeneration in marrow aspirates post-ABMT was delayed in ANLL (p less than 0.05). Neither the nature of the previous induction therapy, nor the status of the blood or bone marrow at the time of collection (CFU-GM and erythroid burst-forming units/ml) nor the stem cell sensitivity to mafosfamide, nor the doses of progenitor cells infused could explain these differences. We interpreted these observations as suggesting that the engraftment potential has been more severely altered in ANLL than in ALL, which may reflect both the intensity of the in vitro treatment and the intrinsic fragility of the stem cell pool in ANLL.     

Evaluation of cytoreductive therapy prior to high dose treatment with autologous bone marrow transplantation in relapsed and refractory Hodgkin's disease

Based on observations that bulky disease at autologous bone marrow transplantation (ABMT) may be correlated with poor outcome in Hodgkin's disease, we have assessed the ability of conventional-dose chemoradiotherapy to reduce tumour burden to a minimum prior to ABMT. Thirty-seven patients with relapsed or refractory Hodgkin's disease referred for intensive therapy and ABMT were treated initially with one to five cycles of DHAP chemotherapy. All patients had previously received MOPP and ABVD chemotherapy or similar regimens. Four patients achieved complete remission (CR) and 12 partial remission (PR), for a total response rate of 43%. Eight partial responders and four non-responders to DHAP achieved significant further tumour reduction with local radiotherapy (five CR, seven PR). Six of 10 non-responders to DHAP responded to alternative salvage chemotherapy (mini-BEAM, CEP or augmented CVP). Overall, 24/37 patients (65%) achieved effective cytoreduction (nine CR, 15 PR with minimal disease) and have proceeded to ABMT. Patients with bulky disease at relapse or limited stage (II, IIIA) at diagnosis were less likely to respond to DHAP, but some of these could be cytoreduced with alternative therapy. In addition, the number of prior chemotherapy regimens correlated inversely with likelihood of response to DHAP. The results indicate that approximately two-thirds of patients with Hodgkin's disease who relapse after MOPP and ABVD-like regimens can achieve effective cytoreduction with conventional-dose chemoradiotherapy and proceed to ABMT in CR or PR with minimal disease.