REL-positive double minute chromosomes in follicular lymphoma.
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Adult↗
Biomedical subjects
A P Rapoport
Publications and source records attributed to A P Rapoport.
Autologous stem cell transplantation followed by consolidation chemotherapy for patients with multiple myeloma.
Although high-dose therapy and autologous stem cell transplant (ASCT) is superior to conventional chemotherapy for treatment of myeloma, most patients relapse and the time to relapse depends upon the initial prognostic factors. The administration of non-cross-resistant chemotherapies during the post-transplant period may delay or prevent relapse. We prospectively studied the role of consolidation chemotherapy (CC) after single autologous peripheral blood stem cell transplant (auto-PBSCT) in 103 mostly newly diagnosed myeloma patients (67 patients were < or =6 months from the initial treatment). Patients received conditioning with BCNU, melphalan+/-gemcitabine and auto-PBSCT followed by two cycles of the DCEP+/-G regimen (dexamethasone, cyclophosphamide, etoposide, cisplatin+/-gemcitabine) at 3 and 9 months post-transplant and alternating with two cycles of DPP regimen (dexamethasone, cisplatin, paclitaxel) at 6 and 12 months post-transplant. With a median follow-up of 61.2 months, the median event-free survival (EFS) and overall survival (OS) are 26 and 54.1 months, respectively. The 5-year EFS and OS are 23.1 and 42.5%, respectively. Overall, 51 (49.5%) patients finished all CC, suggesting that a major limitation of this approach is an inability to deliver all planned treatments. In order to improve results following autotransplantation, novel agents or immunologic approaches should be studied in the post-transplant setting.
Adult↗
Immunity for tumors and microbes after autotransplantation: if you build it, they will (not) come.
Relapses after autologous stem cell transplants for hematopoietic malignancies are frequent and post-transplant infections continue to cause significant post-transplant morbidity and even mortality. The post-transplant period is typically characterized by low lymphocyte counts and impaired immune cell function. Early restoration of immune function may contribute to better disease control and enhance protection from infections. Indeed the attainment of a 'minimal residual disease' status following high-dose therapy makes the early post-transplant period ideal for the introduction of antitumor immunotherapy. Attempts to generate immunity against tumor and microbial antigens after autotransplantation have included vaccinations, T cell infusions (both resting and activated) and combinations of vaccinations and adoptive T cell infusions. One successful strategy for generating robust immune responses against microbial antigens was the combination of pre and post-transplant immunizations along with an early (post-transplant) infusion of in vivo vaccine-primed and ex vivo co-stimulated autologous T cells. Whether this or similar strategies will lead to the generation of effective antitumor immunity is unknown. The lessons gained from efforts to rebuild immune system function in the setting of autotransplantation may also be applicable to the problem of restoring immunity in other immunodeficient groups such as patients with cancer or HIV disease and the elderly.
Aging↗
A fatal Clostridium infection in an allogeneic stem cell transplant recipient.
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Aged↗
Detection of MOZ-CBP fusion in acute myeloid leukemia with 8;16 translocation.
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Acute Disease↗
Amifostine and autologous hematopoietic stem cell support of escalating-dose melphalan: a phase I study.
This study was conducted to define a new maximum tolerated dose and the dose-limiting toxicity (DLT) of melphalan and autologous hematopoietic stem cell transplantation (AHSCT) when used with the cytoprotective agent amifostine. Fifty-eight patients with various types of malignancy who were ineligible for higher-priority AHSCT protocols were entered on a phase I study of escalating doses of melphalan beginning at 220 mg/m(2) and advancing by 20 mg/m(2) increments in planned cohorts of 4 to 8 patients until severe regimen-related toxicity (RRT) was encountered. In all patients, amifostine 740 mg/m(2) was given on 2 occasions before the first melphalan dose (ie, 24 hours before and again 15 minutes before). AHSCT was given 24 hours after the first melphalan dose. Melphalan was given in doses up to and including 300 mg/m(2). Hematologic depression was profound, although it was rapidly and equally reversible at all melphalan doses. Although mucosal RRT was substantial, it was not the DLT, and some patients given the highest melphalan doses (ie, 300 mg/m(2)) did not develop mucosal RRT. The DLT was not clearly defined. Cardiac toxicity in the form of atrial fibrillation occurred in 3 of 36 patients treated with melphalan doses >/=280 mg/m(2) and was deemed fatal in 1 patient given melphalan 300 mg/m(2). (Another patient with a known cardiomyopathy was given melphalan 220 mg/m(2) and died as a result of heart failure but did not have atrial fibrillation.) Another patient given melphalan 300 mg/m(2) died of hepatic necrosis. The maximum tolerated dose of melphalan in this setting was thus considered to be 280 mg/m(2), and 27 patients were given this dose without severe RRT. Moreover, 38 patients were evaluable for delayed toxicity related to RRT; none was noted. Tumor responses have been noted at all melphalan doses and in all diagnostic groups, and 21 patients are alive at median day +1121 (range, day +136 to day +1923), including 16 without evidence of disease progression at median day +1075 (range, day +509 to day +1638). Amifostine and AHSCT permit the safe use of melphalan 280 mg/m(2), an apparent increase over the dose of melphalan that can be safely administered with AHSCT but without amifostine. Further studies are needed not only to confirm these findings, but also to define the antitumor efficacy of this regimen. Finally, it may be possible to evaluate additional methods of further dose escalation of melphalan in this setting.
Adult↗
Molecular remission of CML after autotransplantation followed by adoptive transfer of costimulated autologous T cells.
Four patients with chronic myelogenous leukemia (CML) that was refractory to interferon alpha (two patients) or imatinib mesylate (two patients), and who lacked donors for allogeneic stem cell transplantation, received autotransplants followed by infusions of ex vivo costimulated autologous T cells. At day +30 (about 14 days after T-cell infusion), the mean CD4+ cell count was 481 cells/microl (range 270-834) and the mean CD8+ count was 516 cells/microl (range 173-1261). One patient had a relative lymphocytosis at 3.5 months after T-cell infusion, with CD4 and CD8 levels of 750 and 1985 cells/microl, respectively. All the four patients had complete cytogenetic remissions early after transplantation, three of whom also became PCR negative for the bcr/abl fusion mRNA. One patient, who had experienced progressive CML while on interferon alpha therapy, became PCR- post transplant, and remained in a molecular CR at 3.0 years of follow-up. All the four patients survived at 6, 9, 40, and 44 months post transplant; the patient who remained PCR+ had a cytogenetic and hematologic relapse of CML, but entered a molecular remission on imatinib. Autotransplantation followed by costimulated autologous T cells is feasible for patients with chronic phase CML, who lack allogeneic donors and can be associated with molecular remissions.
Adoptive Transfer↗
Activity of single-agent melphalan 220-300 mg/m2 with amifostine cytoprotection and autologous hematopoietic stem cell support in non-Hodgkin and Hodgkin lymphoma.
High-dose chemotherapy using melphalan (HDMEL) is an important component of many conditioning regimens that are given before autologous hematopoietic stem cell transplantation (AHSCT). In contrast to the situation in myeloma, and to a lesser degree acute leukemia, only a very limited published experience exists with the use of HDMEL conditioning as a single agent in doses requiring AHSCT for lymphoma, both Hodgkin lymphoma (HL) and especially non-Hodgkin lymphoma (NHL). Thus, we report results of treating 26 lymphoma patients (22 with NHL and four with HL) with HDMEL 220-300 mg/m(2) plus amifostine (AF) cytoprotection and AHSCT as part of a phase I-II trial. Median age was 51 years (range 24-62 years); NHL histology was varied, but was aggressive (including transformed from indolent) in 19 patients, indolent in two patients and mantle cell in one. All 26 patients had been extensively treated; 11 were refractory to the immediate prior therapy on protocol entry and two had undergone prior AHSCT. All were deemed ineligible for other, 'first-line' AHSCT regimens. Of these 26 patients, 22 survived to initial tumor evaluation on D +100. At this time, 13 were in complete remission, including four patients who were in second CR before HDMEL+AF+AHSCT. Responses occurred at all HDMEL doses. Currently, seven patients are alive, including five without progression, with a median follow-up in these latter patients of D +1163 (range D +824 to D +1630); one of these patients had a nonmyeloablative allograft as consolidation on D +106. Conversely, 14 patients relapsed or progressed, including five who had previously achieved CR with the AHSCT procedure. Two patients, both with HL, remain alive after progression; one is in CR following salvage radiotherapy. Six patients died due to nonrelapse causes, including two NHL patients who died while in CR. We conclude that HDMEL+AF+AHSCT has significant single-agent activity in relapsed or refractory NHL and HL. This experience may be used as a starting point for subsequent dose escalation of HDMEL (probably with AF) in established combination regimens.
Adult↗
High-dose cyclophosphamide with or without etoposide for mobilization of peripheral blood progenitor cells in patients with multiple myeloma: efficacy and toxicity.
The purpose of the study was to examine the yield of CD34(+) cells, response rates, and toxicity of high-dose cyclophosphamide with or without etoposide in patients with multiple myeloma. In total, 77 myeloma patients received either cyclophosphamide 4.5 g/m(2) (n=28) alone or with etoposide 2 g/m(2) (n=49) in a nonrandomized manner, followed by G-CSF 10 microg/kg/day for the purpose of stem cell mobilization. The effects of various factors on CD34(+) cell yield, response rate and engraftment were explored. A median of 22.39 x 10(6) CD34(+) cells/kg were collected on the first day of leukapheresis (range 0.59-114.71 x 10(6)/kg) in 71 (92%) of patients. Greater marrow plasma cell infiltration (P=0.02) or prior radiation therapy (P=0.02) adversely affected CD34(+) cell yield. In total, 45% of patients receiving cyclophosphamide and 56% of those receiving cyclophosphamide/etoposide had at least a minimum response by EBMT criteria. In all, 25% of patients who received cyclophosphamide alone vs 75.5% of patients who received combined chemotherapy required hospitalization mainly for treatment of neutropenic fever. Cyclophosphamide alone is associated with impressive CD34(+) cell yields and clear antimyeloma activity. The addition of etoposide resulted in increased toxicity without significant improvement in CD34(+) cell yield or response rates.
Adult↗
Autologous stem cell transplantation followed by consolidation chemotherapy for relapsed or refractory Hodgkin's lymphoma.
Relapse remains a major cause of treatment failure after autotransplantation (auto-PBSCT) for Hodgkin's disease (HD). The administration of non-crossresistant therapies during the post-transplant period may delay or prevent relapse. We prospectively studied the role of consolidation chemotherapy (CC) after auto-PBSCT in 37 patients with relapsed or refractory HD. Patients received high-dose gemcitabine-BCNU-melphalan and auto-PBSCT followed by involved-field radiation and up to four cycles of the DCEP-G regimen, which consisted of dexamethasone, cyclophosphamide, etoposide, cisplatin, gemcitabine given at 3 and 9 months post transplant alternating with a second regimen (DPP) of dexamethasone, cisplatin, paclitaxel at 6 and 12 months post transplant. The probabilities of event-free survival (EFS) and overall survival (OS) at 2.5 years were 59% (95% CI=42-76%) and 86% (95% CI=71-99%), respectively. In all, 17 patients received 54 courses of CC and 15 were surviving event free (2.5 years, EFS=87%). There were no treatment-related deaths during or after the CC phase. Post-transplant CC is feasible and well tolerated. The impact of this approach on EFS should be evaluated in a larger, randomized study.
Adolescent↗
Autotransplantation for advanced lymphoma and Hodgkin's disease followed by post-transplant rituxan/GM-CSF or radiotherapy and consolidation chemotherapy.
Disease relapse occurs in 50% or more of patients who are autografted for relapsed or refractory lymphoma (NHL) or Hodgkin's disease (HD). The administration of non-cross-resistant therapies during the post-transplant phase could possibly control residual disease and delay or prevent its progression. To test this approach, 55 patients with relapsed/refractory or high-risk NHL or relapsed/refractory HD were enrolled in the following protocol: stem cell mobilization: cyclophosphamide (4.5 g/m(2)) + etoposide (2.0 g/m(2)) followed by GM-CSF or G-CSF; high-dose therapy: gemcitabine (1.0 g/m(2)) on day -5, BCNU (300 mg/m(2)) + gemcitabine (1.0 g/m(2)) on day -2, melphalan (140 mg/m(2)) on day -1, blood stem cell infusion on day 0; post-transplant immunotherapy (B cell NHL): rituxan (375 mg/m(2)) weekly for 4 weeks + GM-CSF (250 microg thrice weekly) (weeks 4-8); post-transplant involved-field radiotherapy (HD): 30-40 Gy to pre-transplant areas of disease (weeks 4-8); post-transplant consolidation chemotherapy (all patients): dexamethasone (40 mg daily)/cyclophosphamide (300 mg/m(2)/day)/etoposide (30 mg/m(2)/day)/cisplatin (15 mg/m(2)/day) by continuous intravenous infusion for 4 days + gemcitabine (1.0 g/m(2), day 3) (months 3 + 9) alternating with dexamethasone/paclitaxel (135 mg/m(2))/cisplatin (75 mg/m(2)) (months 6 + 12). Of the 33 patients with B cell lymphoma, 14 had primary refractory disease (42%), 12 had relapsed disease (36%) and seven had high-risk disease in first CR (21%). For the entire group, the 2-year Kaplan-Meier event-free survival (EFS) and overall survival (OS) were 30% and 35%, respectively, while six of 33 patients (18%) died before day 100 from transplant-related complications. The rituxan/GM-CSF phase was well-tolerated by the 26 patients who were treated and led to radiographic responses in seven patients; an eighth patient with a blastic variant of mantle-cell lymphoma had clearance of marrow involvement after rituxan/GM-CSF. Of the 22 patients with relapsed/refractory HD (21 patients) or high-risk T cell lymphoblastic lymphoma (one patient), the 2-year Kaplan-Meier EFS and OS were 70% and 85%, respectively, while two of 22 patients (9%) died before day 100 from transplant-related complications. Eight patients received involved field radiation and seven had radiographic responses within the treatment fields. A total of 72 courses of post-transplant consolidation chemotherapy were administered to 26 of the 55 total patients. Transient grade 3-4 myelosuppression was common and one patient died from neutropenic sepsis, but no patients required an infusion of backup stem cells. After adjustment for known prognostic factors, the EFS for the cohort of HD patients was significantly better than the EFS for an historical cohort of HD patients autografted after BEAC (BCNU/etoposide/cytarabine/cyclophosphamide) without consolidation chemotherapy (P = 0.015). In conclusion, post-transplant consolidation therapy is feasible and well-tolerated for patients autografted for aggressive NHL and HD and may be associated with improved progression-free survival particularly for patients with HD.
Adult↗
A 78-year-old man with pancytopenia and abnormal lymphocytes.
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Aged↗
Encouraging preliminary results in 12 patients with high-risk haematological malignancies by omitting graft-versus-host disease prophylaxis after allogeneic transplantation.
Immunosuppressive therapy, routinely given after allogeneic transplantation to modulate graft-versus-host disease (GVHD) may have an adverse effect on the graft-versus-tumour (GVT) effect. Twelve patients with high-risk haematological malignancies were given cyclophosphamide, total body irradiation and antithymocyte globulin followed by peripheral blood stem cell grafts from HLA-identical siblings without prophylactic immunosuppression. At the earliest clinical evidence of GVHD, patients were treated with high-dose solumedrol and tacrolimus. Prompt haematological recovery [absolute neutrophil count (ANC) > 1.0 x 109/l] was observed (median time 9 d). All patients developed grade III-IV GVHD (median onset 9 d), involving the skin (11), intestine (five) and liver (three). Of nine evaluable patients, seven developed chronic GVHD [extensive (six), limited (one)]. Six patients died 1-6.5 months after transplantation. Three patients died from treatment-related complications, two from acute GVHD and one from relapsing disease. The remaining six patients are alive 5-26 months after transplantation, five in complete remission and one myeloma patient in very good partial remission. In conclusion, omission of post-transplantation GVHD prophylaxis is feasible, does not lead to graft failure or a high incidence of uncontrollable GVHD and appears to be associated with encouraging clinical responses in a group of patients with high-risk disease features.
Acute Disease↗
Treatment of chronic myelogenous leukemia with autologous bone marrow transplantation followed by roquinimex.
Unmanipulated autologous bone marrow transplant (ABMT) offers patients with chronic myelogenous leukemia (CML) a long-term survival of 10%, at best. Immunotherapy has a role in the myeloid leukemias, and there is increasing evidence that of all hematopoietic neoplasms, CML may be the most susceptible to immune regulation. Roquinimex is known to enhance T cell, NK cell and macrophage activity. A phase II study was initiated in March 1992 to evaluate the role of roquinimex in Ph chromosome-positive CML post ABMT. Patients were conditioned with busulfan/ cyclophosphamide followed by reinfusion of unmanipulated Ph-positive bone marrow stem cells (>1 x 108 NBC/kg). When engraftment of neutrophils (ANC) reached 100/microl, patients received oral roquinimex twice weekly, escalating to a maximal dose of 0.2 mg/kg in 2 weeks. Seventeen patients have entered the study; 11 in first chronic phase (CP1); two in second chronic phase (CP2) and four in accelerated phase (AP). All required significant myelosuppressive therapy prior to ABMT to maintain stable blood counts and most had also received prior interferon therapy. All patients survived the transplant. Subsequent toxicity consisted mainly of musculoskeletal aches and peripheral edema. Additionally, specific skin changes were observed including graft-versus-host-like disease and eccrine sweat gland necrosis. Eight out of 17 patients are alive 28-60 months post ABMT. Of the nine patients who died, two were in CP2 and three in AP. All patients in CP1 went into a complete hematological remission post ABMT and seven of the 11 patients had at least a major cytogenetic response (greater than 65% Ph-negative metaphases) at 1 year or beyond and four of the 11 patients had a complete cytogenetic response at 2 years or beyond. Cytogenetic response post transplant often developed over time and did not simply represent post ABMT engraftment with Ph-negative cells. The clinical and cytogenetic data in these patients are encouraging and suggest that roquinimex may have significant activity when given post ABMT to patients with Ph-positive CML.
Adult↗
Analysis of factors that correlate with mucositis in recipients of autologous and allogeneic stem-cell transplants.
PURPOSE: To identify predictors of oral mucositis and gastrointestinal toxicity after high-dose therapy. PATIENTS AND METHODS: Mucositis and gastrointestinal toxicity were prospectively evaluated in 202 recipients of high-dose therapy and autologous or allogeneic stem-cell rescue. Of 10 outcome variables, three were selected as end points: the peak value for the University of Nebraska Oral Assessment Score (MUCPEAK), the duration of parenteral nutritional support, and the peak daily output of diarrhea. Potential covariates included patient age, sex, diagnosis, treatment protocol, transplantation type, stem-cell source, and rate of neutrophil recovery. The three selected end points were also examined for correlation with blood infections and transplant-related mortality. RESULTS: A diagnosis of leukemia, use of total body irradiation, allogeneic transplantation, and delayed neutrophil recovery were associated with increased oral mucositis and longer parenteral nutritional support. No factors were associated with diarrhea. Also, moderate to severe oral mucositis (MUCPEAK > or = 18 on a scale of 8 to 24) was correlated with blood infections and transplant-related mortality: 60% of patients with MUCPEAK > or = 18 had positive blood cultures versus 30% of patients with MUCPEAK less than 18 (P =.001); 24% of patients with MUCPEAK > or = 8 died during the transplantation procedure versus 4% of patients with MUCPEAK less than 18 (P =.001). CONCLUSION: Gastrointestinal toxicity is a major cause of transplant-related morbidity and mortality, emphasizing the need for corrective strategies. The peak oral mucositis score and the duration of parenteral nutritional support are useful indices of gastrointestinal toxicity because these end points are correlated with clinically significant events, including blood infections and treatment-related mortality.
Adolescent↗
Treatment of multifocal lymphoma of bone with intensified ProMACE-CytaBOM chemotherapy and involved field radiotherapy.
Primary bone involvement is an unusual extranodal presentation of non-Hodgkin lymphoma (NHL). The optimal treatment for this entity has not been determined. While solitary bone lymphomas can be eradicated with local radiation in 50% of patients, distant relapses occur frequently, and the treatment of patients with multifocal osseous disease, or those presenting with associated soft tissue invasion or adenopathy is even less satisfactory. Over a 4-year period, nine patients with multifocal bone lymphoma were treated with intensified versions of the ProMACE-CytaBOM regimen and involved-field radiation. Seven patients had diffuse large cell histology and two patients had diffuse mixed type. Seven patients survived event-free at a median follow-up of 2.3 years (range .5-3.5). In most survivors, there was little or no change in the abnormal radiographic bone findings despite the clinical response to therapy. In one patient, magnetic resonance imaging (MRI) established that bone infarction rather than relapse of lymphoma was the cause of a new lytic bone lesion that developed during treatment.
Adult↗
Autotransplantation for relapsed or refractory Hodgkin's disease: long-term follow-up and analysis of prognostic factors.
Seventy consecutive patients with refractory or relapsed Hodgkin's disease who received high-dose chemotherapy followed by autologous stem cell rescue were analyzed to identify clinically relevant predictors of long-term event-free survival. High-dose therapy consisted primarily of carmustine (BCNU), etoposide, cytarabine and cyclophosphamide (BEAC). The 5-year Kaplan-Meier event-free survival (EFS) for the entire cohort was 32% (95% confidence interval; 18-45%) with a median follow-up of 3.6 years (range 7 months-7.6 years). The most significant predictor of improved survival was the presence of minimal disease (defined as all areas < or =2 cm) at the time of transplant: the 5 years EFS was 46 vs 10% for patients with bulky disease (P = 0.0002). Other independent predictors identified by step-wise regression analysis included the presence of non-refractory disease and the administration of post-transplant involved-field radiotherapy (XRT). Treatment-related mortality occurred in 13 of 70 patients: nine patients (13%) died within the first 100 days, mainly from cardiopulmonary toxicity. However, only one of 24 patients (4%) transplanted during the last 4.5 years died from early treatment-related complications. While high-dose therapy followed by autotransplantation led to long-term EFS of 50% for patients with favorable prognostic factors, a substantial proportion of patients relapsed, indicating that new therapeutic strategies are needed.
Adult↗
Chronic inflammatory demyelinating polyneuropathy in non-Hodgkin's lymphoma.
A 42-year-old man was diagnosed with large cell non-Hodgkin's lymphoma 3 years after autologous bone marrow transplantation for Hodgkin's disease. The day before beginning systemic chemotherapy, the patient began to have symptoms of a sensorimotor neuropathy characterized by proximal and distal weakness, lower-extremity areflexia, elevated cerebrospinal fluid protein level, and evidence of demyelination on nerve conduction studies. Symptoms progressed despite two courses of intrathecal methotrexate, for possible lymphomatous meningitis, as well as systemic chemotherapy. The diagnosis of chronic inflammatory demyelinating polyneuropathy was made. Daily plasma exchange was performed for a total of 10 treatments with immediate improvement and eventual complete recovery in strength, sensation, and gait. A review of the literature confirms that inflammatory demyelinating polyneuropathy is a highly unusual but important cause of peripheral nervous system dysfunction. The potential for complete response to plasma exchange should be recognized in patients with symptoms, signs, and nerve conduction studies suggestive of chronic inflammatory demyelinating polyneuropathy.
Adult↗