Lymphoblastoid human interferon and low dose IL-2 combined with donor lymphocyte infusion as therapy of a third relapse of CML--a case report

A patient, who was treated twice with donor lymphocyte infusions for relapse of CML after an allogeneic BMT was given lymphoblastoid human alpha-IFN after a third relapse. Further donor lymphocyte infusions were followed by repeated courses of 30 days treatment with a low dosage of IL-2 subcutaneously, alternately with alpha-IFN. This treatment resulted in a hematologic and cytogenetic remission. He also developed a limited degree of chronic GVHD. At the latest follow-up at 20 months after the third course of lymphocyte infusions he is in continuous hematologic and cytogenetic remission. Furthermore, a qualitative PCR analysis for the bcr/abl translocation is negative.     

Importance of mixed chimerism to predict relapse in persistently BCR/ABL positive long survivors after allogeneic bone marrow transplantation for chronic myeloid leukemia

Determination of hematological chimerism could be helpful in understanding the biology of leukemic relapse after allogeneic bone marrow transplant (BMT) for chronic myeloid leukemia (CML), because the detection of malignant residual cells carrying the bcr/abl message by qualitative RT-PCR is of limited value in predicting disease progression for individual patients. We have studied the chimerism pattern and the bcr/abl status by Southern-blot in 15 CML patients (M/F:6/9) transplanted with unmanipulated BM from HLA identical sibling donors, persistently bcr/abl positive by RT-PCR. The median age of the series was 31 years (18-49) and disease status at BMT was: chronic phase: 11, accelerated phase: 3 and blast crisis: 1 patient. Of the 15 patients, 9 are alive and in complete remission (CR), 4 have died in CR and 2 are alive but suffered relapse at + 19 and +26 months post-BMT. The median follow-up is 81 months (13,7-168). Rearrangement of the BCR gene was performed by Southern-blot using P32-labeled transprobe-1. PCR analysis of chimerism was assessed using primers for the following VNTR loci: D1S80, D1S111, 33.1, APO-B, YNZ-22, lambdag3 and DXS52. Seventy-nine samples were analyzed (median per patient 5 (range 2-9)). Thirteen patients showed complete chimerism and lacked BCR rearrangement over time by Southern-blot. The 2 patients who relapsed showed mixed chimera status from +9 and +5 months respectively until the end of the study. Persistent BCR rearrangement was observed in these 2 patients from +12 and +11 months respectively. Our data suggest that mixed chimerism may predict hematologic or cytogenetic relapse by several months in those patients who are persistently PCR-positive post-BMT.     

Prevalence of antibodies to Rickettsia conorii Ricketsia africae, Rickettsia typhi and Coxiella burnetii in Mauritania

A 24-year-old male developed cytogenetic relapse of chronic myeloid leukemia (CML) four years after allogeneic BMT. After a year of treatment with IFN-alpha, he achieved a partial cytogenetic response. Treatment with donor leukocyte infusions (DLI) was given (total dose 1 x 10(8) T lymphocytes/kg). Two months later, he developed acute GVHD (skin and liver), that improved with CsA and methylprednisolone and resulted in cytogenetic remission with complete donor chimerism. One month later he developed rhinocerebral mucormycosis and was successfully treated with surgical debridement and liposomal amphotericin B (total dose 12 g). This is the first case of mucormycosis described after DLI.     

Transvenous cold mapping and cryoablation of the AV node in dogs: observations of chronic lesions and comparison to those obtained using radiofrequency ablation

Lymphocyte transfusion from the marrow donor (DLT) is well established as an effective therapy for relapse of CML post allogeneic BMT. Reports thus far have been mostly limited to patients who received DLT from a matched sibling donor. We compared the efficacy and toxicity of DLT in 30 patients who were treated with cells from their HLA-identical sibling (n = 18) or from their phenotypically HLA-matched unrelated marrow donor (n = 12). The overall probability of obtaining a cytogenetic remission was 69% (95%CI: 51-83%) and was not significantly different between the two groups. The disease stage at the time of DLT was the only factor associated with cytogenetic remission by multivariate analysis; patients treated in cytogenetic or molecular relapse (n = 11) were seven times more likely (RR = 7.4, 95%CI: 2.4-22.4, P = 0.0005) to respond compared to patients treated for hematologic relapse (n = 19). There was a trend towards more acute GVHD II-IV in the unrelated donor group (58 vs 39%, P = 0.09), but the probability of developing extensive chronic GVHD was not significantly different (56 vs 39%, P = 0.4). We conclude that transfusion of donor cells from HLA-matched volunteer donors does not appreciably increase the risk of GVHD compared with transfusion of cells from HLA-identical siblings in patients with CML who relapse following allogeneic BMT. Conversely, there is no evidence for an increased graft-versus-leukemia effect after DLT from volunteer donors.     

Indications, technique and risks in bone marrow transplantation in adulthood

The option of bone marrow transplantation (BMT) significantly improved prognosis of adult patients with hematologic malignancies aged less than 50 years. Allogeneic BMT using the marrow of an HLA-identical family member still provides the most effective method of BMT. Conventional indications for this form of BMT are chronic myeloid leukemia (CML), acute leukemias presenting with adverse risk factors, myelodysplastic syndromes and severe aplastic anemia. If performed early in the disease course (e.g. during the chronic phase of CML or first remission of acute leukemia and MDS) allogeneic BMT cures 50 to 60% of patients. About 20% die of therapy related complications, e.g. graft versus host disease (GvHD), fatal infections or venoocclusive disease of the liver (VOD) and about 20% of patients succumb to relapse of their hematologic disorder. 80% presenting with severe aplastic anemia can be cured, if allogeneic BMT is performed soon after diagnosis without previous immunosuppressive therapy and blood transfusions. BMT with the marrow of a matched unrelated donor or autologous BMT are increasingly used as alternative procedures. A rate of lethal complications as high as 50% hinders rapid extension of BMT with unrelated donors. Therefore, this form of BMT should be restricted to young patients with leukemias, who cannot achieve long-term remission with conventional chemotherapy (in case of acute leukemias) or alpha-interferon (in case of CML). Reconstitution of hematopoiesis is more rapid after peripheral blood stem cell transplantation (PBSCT) compared with autologous BMT. Therefore, PBSCT will replace autologous BMT in most cases. Most favourable results of PBSCT have been reported in patients with malignant lymphomas after relapse or inferior response to primary induction therapy. Due to the higher relapse rate autologous BMT is inferior to allogeneic BMT in leukemia patients. Trials are required to clarify the potential role of myeloablative therapy with stem cell support in the treatment of patients with solid tumors. Many of the preliminary results already published are unsatisfactory and data of larger trials are still lacking. Therefore, BMT or PBSCT cannot be recommended generally for the therapy of patients with solid tumors.     

Allogeneic peripheral blood progenitor cells for treatment of relapse after bone marrow transplantation

Donor leukocyte infusions (DLI) are an effective therapy for patients who relapse with leukemia after bone marrow transplantation (BMT). Severe graft-versus-host disease and prolonged periods of pancytopenia compromise the success of this treatment in a substantial number of patients. We used filgrastim-mobilized peripheral blood progenitor cells (PBPCs), in some cases preceded by cytoreductive therapy, to circumvent some of the problems associated with DLI. Eleven patients (median age 41 years) received a total of 20 donor cell infusions. Their diagnosis was CML in hematological (two patients) or cytogenetic relapse (two patients), six patients suffered from acute myeloid leukemia (AM; n = 5) or Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL Ph+). One patient had multiple myeloma (MM). All six patients with acute leukemias received cytoreductive therapy prior to PBPC infusions; three patients with CML were pretreated with IFN alpha. Four of four patients with CML responded to PBPC infusions and currently are in complete clinical and molecular remission for time periods between 1 and 12 months. Six of six patients with acute leukemias achieved a complete remission. All of them relapsed after a median remission duration of 24 weeks (range 11-49 weeks). Three patients relapsed at extramedullary sites (CNS, testes, skin). Four of six acute leukemia patients received further cytoreductive therapy. All patients responded again and are in complete remission for time periods between 14 and 615 days. Two patients with acute leukemias have died due to dissemination of the disease. The patient with MM did not respond and is alive with disease. Severe (grade III) acute GVHD developed in two of 11 patients, three patients developed grade II disease, six patients did not show any signs of GVHD. Extensive chronic GVHD has developed in two cases to date. Patients with chemotherapy prior to PBPC infusion developed neutropenia and thrombocytopenia with a maximum duration of 20 and 14 days, respectively; prolonged periods of neutropenia did not occur. Two patients developed long-lasting thrombocytopenia in spite of PBPC infusion, in one case followed by leukemic relapse. Repeated courses of chemotherapy and PBPC infusion were generally tolerated well; no early deaths due to treatment-related toxicity or GVHD were observed. We conclude that the use of allogeneic PBPC instead of DLI in patients with relapse after BMT is technically feasible and safe. The efficacy of PBPC infusions seems comparable to DLI in patients with CML. Patients with acute leukemias also achieved complete albeit transient remissions. Aggressive chemotherapy followed by PBPC infusions resulted in only limited duration of cytopenia. The usage of PBPC infusion instead of non G-CSF-mobilized donor cells for treatment of relapse after BMT may reduce pancytopenia-related complications and merits further investigation.     

Treatment of relapse after allogeneic BMT with donor leukocyte infusions in 16 patients

Sixteen patients with relapse after allogeneic BMT were treated with donor leukocyte infusions (DLI) from the original donor. The diagnoses at relapse were: CML in chronic phase (CP) (two patients), CML in accelerated phase (AP) (four patients), AML (four patients), MDS (one patient), ALL (four patients) and relapse of Hodgkin's disease (one patient). The patients received a mean of 5.2 x 10(8) leukocytes/kg with a range of 1.4-12.3 x 10(8) leukocytes/kg. Six patients obtained complete remission (CR), one with CML in CP, three with CML in AP, one MDS and one ALL. Partial remission (PR) was seen in three patients, one patient with CML in AP, one with AML and one with Hodgkin's disease. Seven patients had no response (NR) to the infusions, including one patient with CML in CP transplanted with a syngeneic donor. Four patients developed marrow hypoplasia after DLI (three CR and one PR) and two patients (ALL with CR and MDS with CR) were hypoplastic at relapse and marrow hypoplasia continued after DLI. GVHD occurred without GVL, but GVL only occurred in one patient with absence of GVHD. Eleven patients died of leukemia, six patients are alive. Three patients with CML are in CR 12, 12 and 32 months after DLI and one patient with ALL is in CR 15 months after DLI.     

Donor lymphocyte infusion for the treatment of relapse after allogeneic hematopoietic stem cell transplantation

The results of donor lymphocyte infusion (DLI) for treatment of relapse after bone marrow transplantation (BMT) are reviewed. Durable complete remission can be achieved at the molecular level for a majority (more than 70%) of patients with CML, when treated at early relapse. Results are less favourable for acute leukemias, although useful responses have been reported. Data are scarce though promising for myelodysplastic syndromes and multiple myeloma. Major treatment-associated toxicities are GVHD and bone marrow aplasia. The latter complication can be predicted by evaluating the level of residual donor-derived hematopoiesis. Modification of infused cells (CD8 negative selection or transduction with a suicide gene), addition of peripheral blood stem cells, and early implementation of escalating doses may counteract the complications and increase the response rate. Response rate is variably influenced by the presence of chronic GVHD after initial BMT, T-cell depleted BMT, underlying disease and stage at relapse, and the level of mixed chimerism. DLI is a direct demonstration of the graft-versus-leukemia effect (GVL). Because GVL after BMT is sometimes the predominant cause of cure, it may be advisable in such situations to redirect the conditioning regimens for BMT towards engraftment and less immediate cytotoxicity.     

Detection of BCR/ABL RNA transcripts using the polymerase chain reaction is highly predictive for relapse in patients transplanted with unrelated marrow grafts for chronic myelogenous leukaemia

Relapse after allogeneic bone marrow transplantation (BMT) for chronic myelogenous leukaemia (CML) is thought to result from residual leukaemia cells which survive the intensive conditioning regimen and are not eradicated by donor-derived immune effector cells capable of mediating a graft-versus-leukaemia (GVL) effect. Early relapse can be detected using highly sensitive assays such as the polymerase chain reaction (PCR) which have been shown to have predictive value for subsequent relapse in selected patient populations. The validity of PCR for predicting CML relapse in unrelated marrow transplant recipients where the GVL effect appears to be augmented due to increased HLA disparity between donor and recipient, however, has not been well defined. In this study we assessed the prognostic value of PCR in a cohort of 52 patients transplanted with T-cell-depleted unrelated marrow grafts for CML. The actual probability of relapse at 3 years was 71% in patients with at least one positive assay versus 6% in patients with no positive assays post-transplant. Patients with one or more positive assays at any time post-transplant had a 56-fold increased risk of relapse which was significantly higher (P=0.0002) than that observed in patients who remained persistently PCR negative. Moreover, PCR detected relapse a median of 5 months earlier than cytogenetic analysis in a subgroup of patients in whom concurrent sampling had been performed. These data validate the use of PCR as a prognostic test in this patient population and may help to identify a cohort of patients to be considered as candidates for pre-emptive adoptive immunotherapy.     

Adoptive immunotherapy with donor mononuclear cell infusions to treat relapse of acute leukemia or myelodysplasia after allogeneic bone marrow transplantation

Relapse remains a significant problem after allogeneic bone marrow transplantation (BMT). For patients with relapsed chronic myelogenous leukemia (CML), infusions of donor mononuclear cells (MNC) provide a potent graft-versus-leukemia (GVL) reaction inducing complete remissions in the majority of patients. Little is known about the efficacy of donor MNC infusions for patients who relapse with other diseases. We have studied the GVL effects of donor MNC in eight patients with relapsed acute leukemia or myelodysplasia (MDS). One patient with relapsed MDS achieved complete remission and another patient had a transient response. Five of six non-responders died of progressive leukemia and one non-responder died of complications during second BMT. Three patients developed grade I-II acute GVHD responsive to immunosuppression. These data, and review of the literature, suggest that GVL induction with donor MNC infusions is less effective for patients with relapsed acute leukemia than for patients with relapsed CML; too few patients with relapsed MDS have been treated to draw definite conclusions. However, some patients respond, and given the high mortality associated with alternative procedures such as second BMT, donor MNC infusions are a reasonable approach for relapsed acute leukemia and MDS after allogeneic BMT.     

Cytogenetic abnormalities in primary myelodysplastic syndrome are highly predictive of outcome after allogeneic bone marrow transplantation

Allogeneic bone marrow transplantation (BMT) is the only curative therapy available for patients with myelodysplastic syndrome (MDS). In an attempt to identify prognostic factors influencing outcome, we collected data retrospectively on 60 consecutive adult patients who had undergone BMT at our center for primary MDS or acute myelogenous leukemia evolving from preexisting primary MDS (sAML). Patients were divided into subgroups according to cytogenetic abnormalities based on a recently described International MDS Workshop categorization system. The 7-year actuarial event-free survival (EFS), relapse rate, and nonrelapse mortality (NRM) for all patients were 29% (95% confidence interval [CI], 16% to 43%), 42% (CI, 24% to 67%), and 50% (CI, 37% to 64%), respectively. The EFS for the good-, intermediate-, and poor-risk cytogenetic subgroups were 51% (CI, 30% to 69%), 40% (CI, 16% to 63%), and 6% (CI, 0% to 24%), respectively (P = .003). The corresponding actuarial relapse rates were 19% (CI, 6% to 49%), 12% (CI, 2% to 61%), and 82% (CI, 48% to 99%), respectively (P = . 002) with no difference in NRM between the subgroups. Univariate analysis showed cytogenetic category, French-American-British (FAB) subtype, and graft-versus-host disease (GVHD) prophylaxis used to be predictive of relapse and EFS. In multivariate analysis, only the cytogenetic category was predictive of EFS, with the relative risk of treatment failure for the good-, intermediate-, and poor-risk cytogenetic subgroups being 1.0, 1.5, and 3.5, respectively (P = . 004). For adults with primary MDS and sAML, even after BMT, poor-risk cytogenetics are predictive of an unfavorable outcome; novel treatment strategies will be required to improve results with allogeneic BMT in this patient population.     

Allogeneic cell therapy with donor peripheral blood cells and recombinant human interleukin-2 to treat leukemia relapse after allogeneic bone marrow transplantation

Allogeneic bone marrow transplantation (BMT) is the only effective treatment for hematologic malignancies resistant to conventional chemotherapy. Until recently, no cure existed for patients who relapsed post-BMT. We present our long-term observations on remission induction, after relapse post-BMT, by allogeneic cell therapy (allo-CT) and the feasibility of remission induction in allo-CT-resistant patients by activation of antileukemia effector cells with recombinant human interleukin-2 (rhIL-2) in vitro and in vivo. The longest observation of successful allo-CT (event-free survival, greater than 8 years) was made in a patient with resistant pre-B lymphoblastic leukemia who received infusions with graded increments of donor (female) peripheral blood lymphocytes (PBL) as soon as bulky hematologic and extramedullary relapse was noticed early post-BMT. The patient is currently without evidence of residual host (male) cells as determined by polymerase chain reaction (PCR). Of 17 patients with acute and chronic leukemia in relapse after BMT, 10 were reinduced into complete remission. Four patients with cytogenetic relapse responded to allo-CT alone, while five of six patients with overt hematologic relapse responded only after additional activation of donor with rhIL-2. Allo-CT can, therefore, successfully reverse chemoradiotherapy-resistant relapse of both acute and chronic leukemia. Moreover, in patients resistant to donor lymphocyte infusion, remission can be accomplished by additionally activating donor PBL in vitro and/or in vivo with rhIL-2. Based on our observations, after BMT, allo-CT should be considered the treatment of choice for patients with hematologic malignancies resistant to conventional anticancer modalities. Allogeneic activated cell therapy (allo ACT) should be considered for patients with tumor cells resistant to allo-CT. Although allo-CT, followed if indicated by allo-ACT, can be effective for patients with overt hematologic relapse, reversal of persistent minimal residual disease or documented molecular/cytogenetic relapse early after BMT may also be considered as a possible indication for allo-CT.     

Developments in the treatment of patients with chronic myeloid leukemia

In the treatment of chronic myelocytic leukaemia (CML) allogeneic bone marrow transplantation (BMT) from a sibling donor is the treatment of choice in patients younger than 50 years; the overall 5-year survival is about 60%. Donor lymphocyte infusion without chemotherapy may serve as an efficacious therapy for recurrence of CML after allogeneic BMT. Application of allogeneic BMT from a matched unrelated donor is increasing, but the outcome is still inferior to that of sibling BMT, largely due to more severe and more frequent complications. Treatment with interferon-alpha has been shown to prolong the overall median survival, but especially in a subgroup of patients (about 15%) who achieve a major cytogenic response. Combination of interferon-alpha and low-dose cytarabine leads to increased survival and a better cytogenic response than interferon-alpha alone. Current investigations are aimed at further improving survival and cytogenic response by using more intensive chemotherapy, such as high-dose cytarabine, followed by interferon-alpha maintenance therapy.     

Chronic myelogenous leukemia and acute promyelocytic leukemia: new bone marrow transplantation options

PURPOSE/OBJECTIVES: To describe new bone marrow transplantation (BMT) options for chronic myelogenous leukemia (CML) and acute promyelocytic leukemia (APL), as well as their applications and prognoses, and to describe the role of the oncology nurse in caring for the BMT recipient and options for future nursing research. DATA SOURCES: Published articles, book chapters, and personal experience. DATA SYNTHESIS: Various pretransplant agents and methods are under investigation to improve the outcome and reduce the costs of allogeneic and autologous BMT and peripheral blood progenitor cell (PBPC) transplants. Preliminary results of current studies indicate that autologous BMTs and PBPC transplants have merit as a treatment option in patients with AML and require further research. For patients with APL, BMT usually is reserved for those who fail to achieve or relapse after achieving remission with chemotherapy. Preliminary data show that patients with CML and APL who receive a PBPC transplant engraft more rapidly with decreased morbidity and mortality. CONCLUSIONS: BMT options for patients with CML and APL continue to evolve as advances in pretransplant methods and symptom management become capable of improving the outcome, decreasing costs, and shifting patient care to the outpatient and homecare settings. IMPLICATIONS FOR NURSING PRACTICE: Understanding the marrow transplant options available to patients with CML and APL is essential for nurses. They must stay informed about ongoing improvements in pretransplant processes and symptom-management procedures that reduce BMT morbidity and mortality. Inpatient and outpatient nurses need to collaborate and participate in nursing research to find better ways of providing the best care possible for patients.     

Allogenic bone marrow transplantation in the treatment of malignant hematologic disease

We have treated 28 patients (pts) with malignant hematological diseases with allogeneic bone marrow transplantation (BMT). 18 pts had acute lymphoblastic (ALL) and non lymphoblastic leukemia (ANLL), 5 chronic myeloid leukemia (CML), 2 severe aplastic anemia (SAA), 1 myelodisplasia, 1 Fanconi's anemia and 1 advanced Non Hodgkin's lymphoma. All but three received the graft from HLA identical sibling donors. We used conditioning with total body irradiation and chemotherapy (cyclophosphamide, cytarabine and etoposide) in 17 pts and chemotherapy alone in 11. 24 pts had full hematological recovery 18 to 25 days post BMT. 15 pts died after BMT as a consequence of toxicity or early infection (4), graft failure (2), graft versus host disease (4) or relapse (5). Actuarial event free survival for the group with favorable prognosis (SAA, ALL and ANLL in first or second remission and CML in chronic phase) is 57% at 36 months. Allogeneic BMT is an effective and feasible therapeutic procedure for selected patients with hematological malignancies.     

Infusion of donor peripheral blood mononuclear cells to treat relapse after transplantation for chronic myelogenous leukemia

Until recently, the only curative therapy for patients with chronic myelogenous leukemia (CML) who relapse after allogeneic bone marrow transplantation (BMT) has been second allogeneic BMT. Recently, donor mononuclear cells have been given to patients with relapsed CML to induce a potent graft-versus-leukemia reaction and re-establish complete remissions in the majority of patients without the need for a second transplant. The extraordinary success of donor mononuclear cell infusions shows that it is possible to manipulate and harness the graft-versus-leukemia (GVL) reaction for clinical benefit. The identity of the effector cells and target antigens is unclear, but intensive investigation is beginning to define the complex cytokine and cellular interactions that mediate GVL reactivity. Current clinical trials are investigating strategies that will retain and enhance the GVL effects while limiting toxicity from this therapy. Ultimately, the ability to harness the GVL potential of allogeneic donor cells without excessive toxicity from graft-versus-host disease will be a central challenge in BMT and cellular immunotherapy.