Significance of detection of occult non-Hodgkin's lymphoma in histologically uninvolved bone marrow by a culture technique.

Prolonged disease-free survival of patients with recurrent or resistant non-Hodgkin's lymphoma (NHL) has been achieved with high-dose therapy followed by autologous bone marrow transplantation (ABMT). A concern with the use of ABMT is that the marrow that is reinfused may contain undetected NHL cells with the potential to reestablish metastatic disease in the recipient. Using a culture technique that is sensitive for detecting occult lymphoma cells in BM, we analyzed histologically normal marrow harvests from 59 consecutive patients with intermediate- or high-grade NHL who were candidates for high-dose therapy and ABMT. The culture results indicated that 22 of the patients had occult lymphoma in their marrow. Forty-three patients underwent high-dose therapy followed by ABMT. Twenty-four achieved a complete clinical remission. Those with occult lymphoma in their harvests (11 patients) continued to relapse for up to 3 years, whereas no relapses were observed beyond 8 months in 13 patients receiving marrow that did not contain detectable lymphoma cells using the culture technique. The relapses in the patients who achieved a complete remission occurred at sites of prior bulky disease rather than at new sites, suggesting that the ability to detect occult lymphoma cells in marrow is a marker of biologic aggressiveness and/or resistance to therapy, or that the reinfused cells could only grow in previously involved sites. The detection of lymphoma cells in marrow used for ABMT is an important adverse prognostic factor, and appears to be independent of other clinical predictors of outcome such as sensitivity or resistance of disease to prior chemotherapy.     

Autologous bone marrow transplantation in follicular non-Hodgkin's lymphoma before and after histologic transformation

Patients with disseminated follicular non-Hodgkin's lymphoma (NHL) are only occasionally cured with standard chemotherapy regimens. Although most of these tumors are initially responsive to chemotherapy, in 40% to 70% of patients the lymphoma will eventually transform to an NHL of higher grade malignancy and a poorer prognosis. We treated 18 patients having an original diagnosis of follicular NHL with high-dose therapy and autologous bone marrow transplantation. The lymphomas of 10 of the patients had already undergone histologic transformation and eight still had a follicular histologic pattern. The former group had been followed for a longer time from the diagnosis of NHL and had been more extensively treated with conventional chemotherapy regimens. All eight patients with follicular NHL at the time of transplantation are alive for 246+ to 1,804+ days and seven of the patients are in complete remission. In contrast, of the 10 patients in histologic transformation only 1 is alive and in CR. This reflects the inability of these patients to tolerate the high-dose chemotherapy and myelosuppression as well as resistance of their lymphoma to this therapy. This difference in survival between the two groups was highly significant (P = .002). We conclude that the outcome of patients with follicular NHL transplanted early before histologic transformation is better than for those who are transplanted later in the course of their illness. Because of the relapsing behavior of follicular NHL, a longer follow-up is necessary to prove any impact on the natural history of the disease.     

High-dose therapy supported with immunomagnetic purged autologous bone marrow in high-grade B cell non-Hodgkin's lymphoma.

From August 1987 to March 1995, 25 patients with high-grade B cell non-Hodgkin's lymphoma (NHL) were treated with high-dose therapy (HDT) followed by bone marrow purged with immunomagnetic beads. At the time of transplantation, 20 patients were in sensitive relapse and five in first complete or partial remission. Ten patients had secondary high-grade NHL transformed from low-grade NHL. The HDT consisted of TBI followed by high-dose cyclophosphamide. All patients engrafted, except for two patients with early treatment-related death. Eleven patients relapsed, of whom nine died of lymphoma, and two are alive in new CR. The estimated event-free and overall survivals at 5 years were 40% and 48%, respectively, with a median follow-up of 48 months (range 1-123). Eight of the tumours contained the translocation t(14;18) at the major breakpoint region (MBR) of BCL-2. In these patients the presence of tumour cells in the bone marrow graft before and after purging were assessed by PCR. Four of five patients infused with non-detectable minimal residual disease in their autografts are in complete remission, while two of three patients reinfused with t(14;18) positive cells after purging, experienced a fast and aggressive relapse. As found by others, our data suggest that reinfusion of tumour-free autografts obtained by efficient in vivo purging using chemotherapy before harvesting, and/or by in vitropurging of the stem cell products, influence the patients remission status after HDT.     

Autologous bone marrow transplantation for high-grade lymphoid malignancy using melphalan/irradiation conditioning without marrow purging or cryopreservation. The Northern Regional Bone Marrow Transplant Group

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.     

High-dose therapy followed by autologous bone marrow transplantation (ABMT) in previously untreated non-Hodgkin's lymphoma

13 previously untreated patients with poor prognosis non-Hodgkin's lymphoma (NHL) underwent high-dose therapy followed by autologous bone marrow transplantation (ABMT). All patients experienced a great cytoreductive effect and 9 of them reached a complete remission (mean duration 32 months). The best results were observed in patients with more limited disease and in those without symptoms. 7 patients still remain in complete unmantained remission 15-46 months from the transplant. The probability of survival is 74% at 46 months. No therapy-related deaths were recorded. In differentiating our preliminary approach, we propose high dose therapy followed by ABMT as induction phase in patients with stage II and as consolidation after first line therapy in patients with stages III-IV. Further studies are warranted to determine which type of lymphoma may benefit more and which conditioning regimens may improve the remission rate.     

时辰高剂量化疗联合自体骨髓移植治疗非霍奇金淋巴瘤的长期随访

目的　探讨在自体骨髓 (造血干细胞 )移植技术支持下应用时辰高剂量的环磷酰胺、足叶乙甙、阿糖胞苷和表阿霉素等组成 COAE预处理化疗方案治疗预后差的中高度恶性非霍奇金淋巴瘤 (NHL )的疗效。方法　观察 11例 NHL患者应用该项治疗后造血与免疫功能重建、长期无病生存率、毒副作用及移植相关死亡等 ,选用COX回归模型分析性别、年龄、预处理方案、分期、移植时状态等对无病生存时间的影响。结果　所有患者均获得造血与免疫功能重建。随访 1、3、5年 ,无病生存率分别为 81.8%、6 3.6 %、5 4 .5 % ,最长存活 9年。 5例复发(4 5 .4 % )。无移植相关死亡。结论　该法在给药时间上进行了创新 ,提高了疗效 ,减低了高剂量化疗的毒副作用。该法作为有不良预后因素的中高度恶性 NHL患者诱导化疗达完全缓解后强化治疗手段的远期疗效显著 ,优于常规化疗 ,能够改善生存率     

Autologous hematopoietic cell transplantation non-Hodgkin's lymphoma: 100 month follow-up

One hundred and ten adult patients with non-Hodgkin's lymphoma (NHL) received an autologous hematopoietic cell transplant (ABMT) from 1988 to 1993. All received a uniform preparative regimen of cyclophosphamide, BCNU and etoposide (CBV). Twenty-one percent had low grade histologies, 54% intermediate grade, and 25% high grade. Median follow-up of 48 survivors is 100 months. Kaplan-Meier 10 year overall survival and relapse-free survival for the entire group is 42% and 32%, respectively. Fifty patients were in complete remission 2 years post transplant. With additional follow-up, patients with high grade malignancies are cured, while patients with intermediate or low grade histologies were at continued risk of relapse up to 5 years post transplant. Of 39 patients in complete remission 5 years post transplant, none have relapsed with additional extended follow-up. We conclude that patients with NHL treated with ABMT, if in CR 5 years post transplant, are at very low risk of relapse with extended follow-up, suggesting the possibility of cure for all histologies, including those with low grade NHL.     

Eradication of polymerase chain reaction detectable immunoglobulin gene rearrangement in non-Hodgkin's lymphoma is associated with decreased relapse after autologous bone marrow transplantation

In B-cell non-Hodgkin's lymphoma (NHL), as in other B-cell malignancies, clonal rearrangement of the third complementarity determining region (CDR III) of the immunoglobulin heavy chain gene (IgH) provides a useful marker for the detection of minimal residual disease (MRD) after treatment. To determine the clinical utility of IgH polymerase chain reaction (PCR), we analyzed peripheral blood (PB) and bone marrow (BM) samples from 25 patients with NHL with no PCR detectable chromosomal rearrangement who have undergone autologous bone marrow transplantation (ABMT). Patients with histologic bone marrow infiltration at the time of bone marrow harvest were selected for study since this provided us with diagnostic tissue samples. As an initial strategy DNA was amplified using consensus variable (VH) and joining (JH) region primers. In those cases failing to amplify using consensus region primers, PCR was performed using a panel of VH family-specific framework region 1 (FR1) primers. The clonal products were directly sequenced. From the V-N-D region nucleotide sequences, clone specific probes were constructed and used for subsequent detection of MRD. A clonal PCR product could be PCR amplified and directly sequenced in 18 (72%, 90% confidence intervals 54%-86%) of these 25 patients, 8 with diffuse and 10 with follicular NHL. Eight of these 18 patients have relapsed after ABMT. All had detectable lymphoma cells before relapse and the sequence of the CDR III region at the time of relapse was identical to that obtained at the time of ABMT. All 10 patients who remain in complete remission from 18 to 36 months after ABMT had eradication of PCR detectable lymphoma cells after ABMT, although in three patients PCR detectable MRD was detected early after ABMT. We conclude that sequencing and the use of patient specific IgH CDR III oligonucleotides probes provides a simple and highly reliable method to determine the specificity of the IgH PCR technique. The clinical utility of this technique is demonstrated by the finding that eradication of PCR detectable lymphoma cells in these patients is associated with decreased relapse after ABMT (P = .0002).     

Long-term follow-up of autologous bone marrow transplantation in patients with relapsed follicular lymphoma.

We report the results of high-dose chemoradiotherapy and anti-B-cell monoclonal antibody-purged autologous bone marrow transplantation (ABMT) in patients with relapsed indolent follicular lymphoma. Between March 1985 and May 1995, 153 patients underwent ABMT using a uniform ablative regimen with cyclophosphamide and total body irradiation and bone marrow (BM) purging. All patients received multiple chemotherapy regimens before ABMT. At BM harvest, only 30% of patients were in complete remission, and overt BM infiltration was present in 47%. The disease-free survival (DFS) and overall survival (OS) are estimated to be 42% and 66% at 8 years, respectively. Patients whose BM was negative by polymerase chain reaction (PCR) for bcl2/IgH rearrangement after purging experienced longer freedom from recurrence than those whose BM remained PCR positive (P <.0001). Continued PCR negativity in follow-up BM samples was also strongly predictive of continued complete remission (CR). The 12-year survival from diagnosis for these 153 patients is 69%. Considering that the median survival from diagnosis and first recurrence of patients with advanced follicular lymphoma are 8 and 5 years, respectively, our results provide evidence that myeloablative therapy and ABMT may prolong overall survival.     

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.     

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.     

High-dose therapy and autologous bone marrow transplantation in patients with follicular lymphoma during first remission

We report the results of a study in previously untreated advanced stage patients with follicular lymphoma (FL) who underwent uniform induction chemotherapy with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) followed by myeloablative therapy and anti-B-cell monoclonal antibody purged autologous bone marrow transplantation (ABMT). Eighty-three patients with previously untreated, low-grade FL were enrolled. After CHOP induction, only 36% achieved complete remission (CR) and 77 patients underwent ABMT. Before BM harvest, 70 patients had a known t(14;18), as determined by polymerase chain reaction (PCR), and all remained PCR positive in the BM at harvest. After ABMT, the disease-free survival (DFS) and overall survival are estimated to be 63% and 89% at 3 years, respectively, with a median follow-up of 45 months. Patients whose BM was PCR negative after purging experienced significantly longer freedom from recurrence (FFR) than those whose BM remained PCR positive (P = .0006). Continued PCR negativity in follow-up BM samples was also strongly predictive of continued CR. This study suggests that a subset of patients with advanced FL may experience prolonged clinical and molecular remissions following high-dose ablative therapy, although longer follow-up will be necessary to determine potential impact on overall survival.     

Detection of residual lymphoma cells by polymerase chain reaction in peripheral blood is significantly less predictive for relapse than detection in bone marrow

Polymerase chain reaction (PCR) amplification of the t(14;18) has been shown to be a highly sensitive method to detect minimal residual disease in patients with non-Hodgkin's lymphoma (NHL) whose tumors bear this translocation. The ideal tissue source to detect residual lymphoma would be from a previously involved lymph node. However, lymphoid tissue is rarely available once patients achieve complete remission. Although PCR amplification has been used to detect residual lymphoma cells in both bone marrow (BM) and peripheral blood (PB) of patients in complete remission, it is presently unknown whether BM and PB are equivalent tissue sources to detect residual disease. In the present study, we compared the clinical utility of the detection of residual lymphoma in both the BM and the PB of patients with advanced-stage non- Hodgkin's lymphoma before, at the time of, and after high-dose therapy and autologous BM transplantation (ABMT). The detection of residual lymphoma in either the BM or PB was associated with decreased disease- free survival. However, in the present study, 44% of patients who relapsed had no evidence of circulating lymphoma cells in their PB. At the time of BM harvest, PCR-detectable residual lymphoma cells were detected in 211 of 212 patients; although, in a subset of these patients analyzed, lymphoma cells were detected in the peripheral blood of only 49% of patients. When residual lymphoma cells within the autologous BM are infused into the patient these cells are rapidly detectable circulating in the PB in the patient. These cells continue to circulate during the immediate posttransplant period and be detectable in the PB in the majority of patients who are infused with marrow containing residual lymphoma. We conclude that BM is a more informative tissue source than PB in detecting minimal residual disease at the time of and after ABMT, and that contamination of PB early after ABMT appears to be the consequence of reinfusion of lymphoma cells within autologous marrow.     

Ifosfamide,mitoxantrone and etoposide (VIM) as salvage therapy of low toxicity in non-Hodgkin's lymphoma

Abstract: Patients with non-Hodgkin's lymphoma (NHL) who fail to respond to first-line treatment or relapse after having shown complete or partial remission have a poor prognosis, especially in high-grade NHL. Several salvage regimens show considerable toxicity and a poor long-term outcome. In this retrospective study we analyzed data of 55 patients (34 men and 21 women) with a median age of 66 years (range: 18–89). The combination chemotherapy (VIM) consisted of VP-16 (etoposide) 65 mg/m², ifosfamide 650 mg/m² and mitoxantrone 3 mg/m² and was administered on 3 consecutive days along with mesna as uroprotection. Patients were treated for refractory disease or relapse and did not qualify for high-dose chemotherapy and ABMT. Stages according to the An Arbor classification were: stage I/16, II/4, III/8 and IV/37 patients. Thirty-three patients suffered from high-grade and 22 from low-grade NHL. Toxicity (WHO recommendations) was very mild. High-grade NHL showed a better response rate (18/33, 46%) than low-grade NHL (7/22, 36%). Overall response was 41% (12 CR and 11 PR) with a median duration of 36 months (range: 6–57 months). The combination therapy investigated exhibits mild toxicity even in extensively pretreated or elderly patients. The overall response rate of 41% might be improved by increased dosage and growth factor support.     

Intensive cytotoxic therapy followed by autologous bone marrow transplantation for non-Hodgkin's lymphoma of high-grade malignancy

Fourteen patients with non-Hodgkin's lymphoma (NHL) of high-grade malignancy were treated with cyclophosphamide and total body irradiation followed by autologous bone marrow transplantation (ABMT). All patients were pretreated with conventional chemotherapy. Three of four patients with drug-resistant disease achieved complete remission (CR), but relapse occurred within six months. Four patients in partial remission (PR) achieved CR; one died because of sepsis, two relapsed within six months, and one is still in CR 28+ months later. Six were treated in CR, five in first CR, and one in second CR. From these six patients (who received this treatment as consolidation therapy), five are in unmaintained CR seven to 31+ months after ABMT (one patient died of a secondary illness). There were two therapy-related deaths, both in patients with a poor clinical condition. Toxicity of this treatment was mild for those receiving transplants who were in better condition. These preliminary results suggest that intensive cytoreductive therapy followed by ABMT may improve disease-free survival in patients in NHL of high-grade malignancy in CR.     

p53 mutation is associated with progression in follicular lymphomas

The majority of low-grade follicular lymphomas will eventually transform to an aggressive intermediate, or high-grade lymphoma. The molecular mechanisms responsible for this transformation have not been determined. We studied serial biopsies from 34 patients with follicular lymphomas that underwent histologic transformation, for abnormalities of the p53 tumor suppressor gene by a combination of immunohistochemistry, single strand conformation polymorphism analysis (SSCP), and sequencing. We found overexpression of p53 in 10 of the 34 transformed aggressive lymphomas, 9 of which contained mutations identified by SSCP analysis and subsequent sequencing. Matched pretransformation low-grade follicular lymphoma biopsies were available for 7 of the 10 cases. None of six studied by immunohistochemistry showed overexpression of p53 and only 1 of 4 studied by SSCP/sequencing showed the presence of mutation in the pretransformation biopsy. Interestingly, an eighth p53 positive transformed lymphoma recurred with a clonally related, p53 negative low-grade lymphoma 5 years after the patient had achieved a complete remission. Immunohistochemistry also showed that several pretransformation biopsies from p53 positive transformed cases showed rare p53 positive cells and in one case we could document an increase in their number over time. Twenty-five additional low-grade follicular lymphoma biopsies were also examined. Three patients had lymphomas positive for p53 mutation. One of the three subsequently transformed within a year of the biopsy studied; the second patient had an earlier (unavailable) biopsy at a different site that showed transformed histology. The third patient was treated with ProMACE-MOPP combination chemotherapy and attained a complete remission. We conclude that (1) mutations of p53 are associated with histologic transformation in approximately 25% to 30% of follicular lymphomas and (2) p53 positive cells can be detected before histologic transformation, but do not comprise a significant percentage of the neoplastic cell population (identifiable by SSCP) until late in the disease, just before or after histologic progression. Finally, the data also suggest that p53 positive low-grade lymphomas are at risk for progression and that in this subset, aggressive therapy may be warranted.     

Autologous bone marrow transplantation as consolidation therapy for non-Hodgkin's lymphoma patients with poor prognostic features.

Theoretical considerations and preliminary results of clinical trials support the earlier use of autologous bone marrow transplantation (ABMT) in poor prognosis non-Hodgkin's lymphoma (NHL). A prognostic analysis of 50 patients with intermediate or high grade NHL younger than 60 years, who achieved at least one complete remission and were not treated with BMT, was performed. Patients with bulky tumor at diagnosis and/or serum LDH greater than or equal to 600 U/l do poorly with conventional chemotherapy. Twelve patients with these high-risk initial characteristics in first complete remission (CR) and six patients in second or third CR were treated with cyclophosphamide (60 mg/kg x 2) and total body irradiation (1000-1200 cGy) followed by ABMT. Overall disease-free survival was 65% at a median follow-up of 35 months. No differences were found between the first and later CR patients. The rate of toxic death was 11%. Disease-free survival after first CR was better for 1st CR ABMT patients than for a historical chemotherapy control group with similar poor prognosis features (p = 0.008). These results support the use of ABMT in selected, high-risk NHL patients in first CR.     

Factors associated with survival in patients with progressive disease following autologous transplant for lymphoma

Our objectives were to assess survival and predictors for survival among lymphoma patients whose disease had progressed after autologous bone marrow (ABMT) or stem cell transplantation (ASCT). Patients transplanted at Hadassah University Hospital between October 1983 and February 1999 were included. We compared survival of patients with Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) after relapse or progression. Predictors for survival were assessed in a multivariate model. Of 88 transplanted patients with HD and 152 with NHL, relapse/progression occurred in 27 (31%) and 75 (49%), respectively. Median survival postrelapse was 25 months for HD and 7.5 months for NHL (P=0.12). Seven relapsed patients with HD (26%) and 10 (13%) with NHL survived >4 years. In NHL, longer postrelapse survival was associated with indolent histologies (P=0.007). On multivariate analysis, factors associated with survival included attainment of remission postrelapse (for both diseases), use of prophylactic immunotherapy (for HD), LDH level and time from transplant to relapse (for NHL). The short-term prognosis for patients with disease progression postautologous transplant may be somewhat better for HD compared to NHL. Long-term survival is poor in both diseases. However, the survival times in the current study are twice as long as those previously reported. Treatment regimens with the potential for achieving remission may have an impact on survival.     

Effects of Mega-COMLA (cyclophosphamide, cytarabine, vincristine, and methotrexate followed by leucovorin and prednisone) plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) in the treatment of lymphoid neoplasms with very poor prognosis

Treatment results remain very poor for some clinical and histopathologic subsets of patients with aggressive non-Hodgkin's lymphoma. We treated 21 such patients with a high-dose combination chemotherapy regimen [Mega-COMLA (cyclophosphamide, cytarabine, vincristine, and methotrexate followed by leucovorin and prednisone) + CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)] in an attempt to improve disease-free survival. Neoplasms were classified using the Lukes-Collins system. Eight patients had T-cell lymphomas (convoluted lymphocytic lymphoma, four patients; T-cell lymphoma/leukemia, one; and peripheral T-cell lymphoma, three), eight had B-cell lymphomas (immunoblastic sarcoma, five patients; small noncleaved follicular center cell, one; and large noncleaved follicular center cell, two), and five had nontypable large noncleaved cell lymphomas. All patients were previously untreated; 18 of 21 patients had clinical stage III or IV disease. Following induction therapy (4-8 weeks' duration), 16 patients (76%) achieved complete remission, while three had partial remission. Two patients died of sepsis during induction therapy. Eleven of 16 complete responders (69%) remain in complete remission after a median follow-up of 35 months. The actuarial 3-year survival rate is 51% for the entire group. Myelosuppression with this regimen was severe and prolonged, with a median duration of neutropenia (less than 500 cells/microliter) of 14 days. Seven patients (33%) developed severe neuropathy following induction treatment. High-dose induction therapy with this regimen resulted in a high complete remission rate with manageable toxicity. Survival results are encouraging when compared retrospectively to our patients with similar poor-prognosis histologies treated with standard combination chemotherapy. However, the value of this intensive therapy, relative to newer ("third-generation") regimens, can only be established by prospective randomized studies.     

Autologous bone marrow transplantation for children with AML in first remission

In Children's cancer group (CCG) 2891, newly diagnosed patients with AML were randomized between standard and intensive timing induction therapies. Patients in first remission who lacked an HLA matched family donor were randomized between an autologous bone marrow transplantation (ABMT) where marrow was purged with 4 hydroperoxycyclophosphamide and consolidation chemotherapy. One hundred and thirty seven patients received an ABMT. Myeloid and platelet engraftment occurred at a median of 44 and 42 days, respectively. Disease-free survival (DFS), relapse-free survival and overall survival at 8 years post induction were 47% (95% confidence interval (CI): 38-55), 50% (CI: 42-59) and 55% (CI: 46-63), respectively. Multivariate analysis of DFS showed WBC <50 000/microl and having received intensively timed induction therapy were associated with improved DFS. Recipients who received intensive timed induction therapy and whose WBC was less than 50 000/microl had a DFS at 8 years of 62% (CI: 49-73). Conversely, recipients who received intensive timed induction therapy patients whose WBC was > or =50 000/microl had a DFS of 33% (CI: 17-50), P=0.003. The results confirm previous studies that ABMT is effective post remission therapy for pediatric patients with AML in first remission.