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Objectives: Treatment for childhood leukemia requires frequent lumbar punctures (LP) and bone marrow aspirations (BMA), often described by children and parents as more distressing than the disease itself. Findings in schoolchildren and chronic pain samples indicate that increased parental distress may increase parental protective, pain-attending behavior, which is associated with more child pain and distress. However, in the context of invasive medical procedures, it is unknown which parents are likely to become most distressed and engage in pain-attending behavior, and how this impacts the children's experiences. The present study investigated the impact of parental catastrophic thoughts upon parental distress and pain-attending behavior (verbal and nonverbal). Furthermore, the association between parental responses and the children's pain behavior, pain, and distress was examined., Materials and Methods: A total of 46 parents of children with leukemia (range, 0.6 to 15 y) who underwent a LP/BMA procedure participated in this study. Parental catastrophizing was assessed before and parental and child distress was assessed after the LP/BMA procedure. Parental pain-attending behavior and the child's pain behavior were observed before and after the LP/BMA procedure., Results: Findings indicated that heightened parental catastrophic thinking contributed to increased parental distress during LP/BMA and less pain-attending behavior before the LP/BMA procedure, especially in young children. In contrast, heightened distress in parents with high levels of catastrophizing contributed to increased engagement in postprocedural pain-attending behavior. For young children, increased preprocedural pain-attending behavior was related to more child distress, pain, and pain behavior., Discussion: The findings demonstrate the importance of parental catastrophic thinking in understanding their caregiving responses and preparing parents and children for painful invasive medical procedures.

Bone marrow (BM) transplantation (BMT) is one of the treatment strategies for congenital metabolic disease, but leukemia secondary to intensive cytoreductive treatment is a major concern. Besides BM cells, mesenchymal stem cells (MSC) are also used for transplantation. An 8-month-old girl with hypophosphatasia underwent transplantation of haploidentical BM cells followed by two transplants of MSC obtained from her father to facilitate osteogenesis. Fludarabine(Flu)/cyclophosphamide (CPA)/anti-thymocyte globulin were used for myeloablative conditioning, but the patient developed therapy-related leukemia harboring t(9;22)(q34;q11.2); minor BCR-ABL (t-leukemia with Ph) at the age of 32 months. At the age of 40 months she underwent a second BM and third MSC transplant from the same donor. Thereafter, she achieved complete histological and molecular remission. The present case suggests that the combination of cytotoxic agents (Flu/CPA) and MSC led to t-leukemia with Ph as a consequence of chromosome instability and suppression of host anti-tumor immunity., (© 2013 The Authors. Pediatrics International © 2013 Japan Pediatric Society.)

Objective: To review the literature related to nonmyeloablative stem cell transplantation (SCT), and the unique characteristics and patient population to which it applies., Data Sources: Research studies, research and clinical reviews, clinical experience., Conclusion: Nonmyeloablative SCT has demonstrated effective and safe application in a heterogeneous population not otherwise eligible for an allogeneic transplantation. Although many principles are based on those of conventional myeloablative transplantation, the engraftment kinetics, patient selection, and regimen-related complications are distinct., Implications for Nursing Practice: Nurses must be knowledgeable about nonmyeloablative SCT, including the provision of individualized care for a heterogeneous population. This can include non-traditional transplant indications, elderly cancer patients, and those with comorbidities.

Objective: Minimal residual disease (MRD) present in peripheral blood stem cell (PBSC) products of AML patients may contribute to relapse. Our goal was to 1) predict leukemia recurrence based on the frequency of MRD present in PBSC products, 2) establish the efficacy of different purging procedures, and 3) integrate this into a model that enables to predict whether or not to purge., Methods: Minimal residual disease was measured with flow cytometry using leukemia-associated phenotypes as established at diagnosis. Toxicity of purging procedures was established using clonogenic assays. Purging procedures used were cryopreservation, hyperthermia, ether lipid ET-18-OCH3, and combinations., Results: Minimal residual disease in PBSC products correlated significantly with relapse-free survival (n=24, p=0.003). At a cut-off value of 0.05% MRD the relative risk of relapse was 4.6 times lower in the group with less than 0.05% MRD. As measured in 54 PBSC products, the MRD level was less than 0.05% in 17 of 54 cases, between 0.05% and 0.5% in 19 of 54 cases, and higher than 0.5% in 18 of 54 cases. Based on the MRD cut-off of 0.05%, the log tumor reduction needed to achieve this threshold is zero for the 17 of 54 cases in which MRD was below 0.05%, less than or equal to 1 log in 19 of 54 cases, and greater than 1-2 log in 18 of 54 cases. When applying purging with 25 mug/mL ET-18-OCH3 combined with cryopreservation at 10% DMSO and hyperthermia at 42 degrees C combined with cryopreservation at 10% or 4% DMSO, there was greater than or equal to 1 log depletion of AML blasts., Conclusion: This study establishes (1) a threshold level for MRD above which prognosis is worse, (2) that stem cell products from 69% of patients have higher than this "safe" MRD level, and (3) that ET-18-OCH3 and hyperthermia may be used to purge products in part of these patients.

Background: After myeloablative treatment and allogeneic stem cell transplantation (ASCT), patients are kept isolated in the hospital to prevent infections during neutropenia., Methods: So far, 22 patients have been given the choice of being treated at home. Eleven could not be treated at home, and they served as controls. Most of them had haematological malignancies. The donors were 12 HLA-compatible unrelated, 9 HLA-identical siblings and one twin., Results: In the home care group, 3 developed bacteraemia, compared to 9 in the controls (p<0.01). The patient in the home care group had fewer days on total parenteral nutrition (median 3 vs. 24, p<0.001), required fewer erythrocyte transfusions (median 4 vs. 8, p=0.01), fewer days on i.v. antibiotics (median 6 vs. 13 days), and on analgesics (median 0 vs. 15) than the controls (p<0.05). Days with fever, time to engraftment, days with G-CSF and acute GVHD were the same in the two groups. 7/11 patients treated at home were readmitted to the ward for median 3 (0-7) days, due to fever or lack of a caregiver at home. Days to discharge to the out-patient clinic was faster in the group treated at home (median 20 vs 35 days, p<0.01)., Discussion: Patients who were treated at home enjoyed being active and taking a walk when they felt like it. This preliminary report suggests that home care after ASCT is not only safe, but better than isolation in the hospital.

Background: Following hematopoietic cell transplantation, infections (less frequent following autologous rather than allogenic transplantation) are the principle cause of morbidity and mortality., Methods: We present a retrospective study of infectious mortality in 400 patients suffering from malignant haematological affections and having undergone autologous hematopoietic cell transplantation., Results: Among these 400 patients, 29 (7.3%) died from infection. Using multivariate analysis, the only variable associated with the risk of fatal infection was the year of the transplantation., Discussion: This is one of the largest homogeneous series devoted to infectious mortality in patients suffering from malignant haematological affections and having undergone autologous hematopoietic cell transplantation. Some of these patients, considered as low-risk (transitory neutropenia, aged under 60, haematological disease in complete regression, without co-morbidity, presenting fever without site of infection nor sepsis) could eventually be treated at home with parenteral, sequential or perhaps even oral antibiotics.

Purpose of Review: Early trials of high-dose therapy with autologous stem cell transplantation in mantle cell lymphoma were discouraging, with no clear survival advantage attributable to the procedure. Most early series were plagued by small numbers, retrospective designs, and short follow-up. Also, until recently, allogeneic stem cell transplantation was not an option for most mantle cell lymphoma patients who were too old or infirm to tolerate standard conditioning regimens., Recent Findings: New advances in allogeneic transplantation, particularly reduced-intensity conditioning regimens, have increased the availability of this procedure to patients with mantle cell lymphoma. New evidence has emerged during the last several years that suggests autologous stem cell transplantation in first complete remission may provide a survival advantage over conventional chemotherapy in patients with mantle cell lymphoma. Additionally, investigational strategies such as in vivo purging with rituximab and the use of radioimmunotherapy in conditioning regimens may further increase response rates and, hopefully, survival in mantle cell lymphoma patients. Finally, recent studies suggest the existence of a graft-versus-lymphoma effect in mantle cell lymphoma providing strong scientific rationale for the possible curative potential of allogeneic stem cell transplantation in this disease., Summary: This review focuses on recent advances in allogeneic and autologous transplantation for mantle cell lymphoma. Particular emphasis is placed on the role of autologous transplantation in first complete remission, the role of in vivo purging with rituximab, the utility of radioimmunotherapy and, finally, the evolving strategy of reduced-intensity allogeneic stem cell transplantation.

Autologous stem cell transplantation is used to rescue cancer patients from myelosuppression caused by high-dose chemotherapy. However, autologous grafts often contain tumor cells that can contribute directly to relapse. Current purging methods are useful when fewer than 1% tumor cells contaminate the bone marrow, and patients with tumor burdens of >1% are considered ineligible for chemotherapy that necessitates stem cell rescue. Using neuroblastoma (NB) as a model system, we developed a method that is effective even with tumor burdens of 10-25%. Mixtures of NB-1691 NB cells and CD34(+) hematopoietic cells purged by this method showed no evidence of viable tumor cells as assessed by clonogenic assays or reverse transcription-PCR for the NB cell markers tyrosine hydroxylase and N-MYC. The efficacy and lack of toxicity of the method were verified using in vivo mouse models. Severe combined immunodeficient mice that received purged cell preparations containing 10% NB-1691 cells survived without evidence of disease for the observation period (>1 year), whereas mice that received unpurged cells developed disseminated disease requiring euthanasia 73-96 days after injection of cells. No evidence of toxicity to the mice was detected by numerous laboratory values for bone marrow, liver, and kidney function, and no difference was seen in the ability of purged cell mixtures versus unmanipulated CD34(+) cells to reconstitute the marrow of non-obese diabetic severe combined immunodeficient mice. In a pilot study, marrow was obtained from eight patients who had >/=1% metastatic tumor burden. All eight samples were purged to the level of detection by reverse transcription-PCR (samples from seven patients) or clonogenic potential (sample from one patient), whichever assay was used. The described adenovirus/rabbit carboxylesterase/CPT-11 (irinotecan, 7-ethyl-10[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin) virus-directed enzyme prodrug method may be useful for patients whose tumor burdens exceed 1% at the time of stem cell harvest. Assessment of purging efficacy with additional samples from NB patients is ongoing.

The treatment for pediatric cancer can have serious oral complications that adversely affect prognosis. Dental intervention to pediatric cancer patients is crucial in influencing side effects of therapy. This case study will demonstrate the role for oral intervention prior to and during cancer chemotherapy, as well as demonstrate the overall success achieved with interdisciplinary care.

Background: Children with leukemia undergo painful procedures such as lumbar puncture and bone marrow aspiration. To overcome pain, certain units offer total anesthesia; others offer generic support; others offer no preparation at all. Since September, 1997, we have provided leukemic children with art therapy (AT), a nonverbal and creative modality that develops coping skills. Our goal is to prevent anxiety and fear during painful interventions as well as prolonged emotional distress., Procedure: We treated 32 children aged 2-14 years. The modes of AT before, during, and after the punctures were as follows: clinical dialogue to calm children and help them cope with painful procedures; visual imagination to activate alternative thought processes and decrease the attention towards overwhelming reality and raise the peripheral sensitivity gate; medical play to clarify illness, eliminate doubts, and offer control over threatening reality; structured drawing to contain anxiety by offering a structured, predictable reality (the drawing) that was controllable by children; free drawing to allow children to externalize confusion and fears; and dramatization to help children accept and reconcile themselves to body changes., Results: Children hospitalized before September, 1997, exhibited resistance and anxiety during and after painful procedures. By contrast, children provided with AT from the first hospitalization exhibited collaborative behavior. They or their parents asked for AT when the intervention had to be repeated. Parents declared themselves better able to manage the painful procedures when AT was offered., Conclusion: AT was shown to be a useful intervention that can prevent permanent trauma and support children and parents during intrusive interventions., (Copyright 2001 Wiley-Liss, Inc.)

Background: The effect of allogeneic hematopoietic cell transplantation (alloHCT) on hematologic malignancies is based on the graft-versus-malignancy effect. Obtaining this effect with reduced toxicity has been possible by non-myeloablative (NMA) alloHCT. Once mixed chimeric status, and host versus graft with graft versus host tolerance are achieved, further strengthening of chimerism and graft-versus-malignancy effect can be obtained by donor lymphocyte infusions (DLIs) when needed., Methods: The patient group consisted of 13 patients with advanced hematological malignancies: seven had CML, four of them in blastic-, two in chronic- and the remainder in accelerated-phase; four patients with AML, refractory or in second remission state; one patient with primary refractory secondary AML; and one patient with ALL relapsed after alloHCT. Conditioning regimen consisted of fludarabine 30 mg/m(2)/day for 6 days and anti-T-lymphocyte globulin (ATG) 10 mg/kg/day for 4 days as immunosuppressive. Ara-C or Bu or melphalan were used as the cytoreductive component. All transplants were performed using HLA-identical sibling donors' peripheral blood hematopoietic cells, after priming with filgrastim. Post-transplant GvHD prophylaxis was achieved with CsA alone in 10 patients, and with CsA plus mycophenolate mofetil in the last three patients., Results: Median follow-up is 3 months (range, 0-20) for all the patients and 6 months (range, 2-15) for the live patients. Donor chimerism was shown in 10 patients, not regarding any pretransplant feature. DLIs were performed in seven patients after transplantation and two of them achieved complete chimeric status and molecular remission. Two CML patients in blastic phase (CML-BP), and the primary refractory secondary AML patient did not respond to procedure. In four patients, drug therapy in conventional doses was added to post-transplant DLIs for their relapsed or refractory diseases. Two patients with AML in second CR, and another CML-BP patient, relapsed or progressed after transplantation. A patient with CML-BP achieved CR and full donor chimerism after transplantation, but developed refractory post-transplant lymphoproliferative disease in the 19th month. Two patients with refractory AML, one patient with relapsed ALL and two patients with CML in chronic phase were in complete chimeric status and free of disease signs. Acute GvHD, Grade II-III, was observed in five patients, and two of them developed secondary progressive chronic GvHD subsequently. We observed one early death in a platelet transfusion refractory blastic phase CML patient due to intracranial hemorrhage. Procedure-related severe toxicity was not observed, either in standard-risk patients or stem-cell donors., Discussion: Establishing engraftment with donor chimerism was the first successful step in this approach. The second step, which was the result of the graft-versus-malignancy effect, could be seen in most of the patients, but was not sustained in all of them because of the aggressiveness of their malignancy. It can be suggested that the immunotherapeutic efficacy of this approach could be more successful, and with acceptable toxicity, when performed in patients with minimal residual disease. The role of NMA conditioning, and of the treatment in standard disease indications, remains to be determined in further studies.

Bone marrow or stem cell transplantation is an established therapy for haematological malignancies. We report a cytomegalovirus (CMV) IgG +ve 56-year-old patient who underwent autologous rescue with CD34(+) selected peripheral blood stem cells as part of consolidation therapy for multiple myeloma and subsequently developed CMV colitis. In contrast to infection secondary to human immunodeficiency virus (HIV), CMV colitis has not previously been described in this context. We discuss this case and issues arising from it related to the use of CD34+ selected stem cells for transplantation.

Autologous graft-versus-host disease (GVHD) has been frequently reported after cyclosporine A (CsA) administration in the autologous setting. This complication is related to the disruption of self-tolerance mechanisms induced by CsA and may exert an antitumor effect. We report the spontaneous occurrence of autologous GVHD after CD34+-purified peripheral blood progenitor cell transplantation (PBPCT) in 5 out of 24 consecutive patients (20.8%). The syndrome was characterized by skin rash (5/5), pruritus (5/5), eosinophilia (5/5), and fever (2/5) occurring at a median of 37 days (range 22-60) after transplantation. Diagnosis was confirmed by skin biopsy in all patients. The syndrome was self-limiting, lasted a median of 25 days, and did not require treatment. The rate of autologous GVHD was high after CD34+-purified autologous PBPCT. In fact, no autologous GVHD was documented in an historical control of 100 consecutive patients submitted to unmanipulated PBPCT at the same institution. The manipulation of the graft by the purging procedure causes a profound T lymphocyte depletion, thus possibly perturbing the equilibrium between autoregulatory cells and autocytotoxic T cells. These observations add new interest to the antitumor efficacy of autologous GVHD and suggest new questions regarding the role of transplantation for autoimmune diseases.

Alopecia can be a psychologically daunting prospect for people requiring cancer chemotherapy. Fortunately, most patients experience only temporary hair loss. We report the case of a 23-year-old woman with chronic myeloid leukaemia who developed permanent, near-total alopecia of her scalp, eyebrows, eyelashes, axillary and public hair following busulphan and cyclophosphamide chemotherapy which was used as conditioning prior to allogeneic bone marrow transplantation. The histology from a scalp biopsy revealed hair follicle destruction. Topical minoxidil failed to induce significant re-growth.

Background: Autologous stem-cell transplantation has proved curative therapy for relapsed NHL. However, recurrence of underlying disease remains the major cause of treatment failure in this setting., Methods: Development of effective MAb therapy directed against the B cell surface antigen CD20 has added a valuable tool of clearing contaminating lymphoma cells from stem-cell products by either in vitro or in vivo application., Results: Transplantation of successfully in vitro purged bone marrow using Mabs has been correlated with prolonged survival in large Phase-II study. So far, no randomized trial could demonstrate a therapeutic benefit for in vitro purging. The anti-CD20 Mab rituximab has been used for in vivo purging at the time of stem cell collection or peritransplantation. This method has been shown to be safe and feasible. In the majority of patients the combination of rituximab with anti-lymphoma chemotherapy meant the collected stem cell products were free of molecularly-detectable lymphoma cells., Discussion: The increasing ability to kill all lymphoma cells in vivo by regimens including myeloablative therapy renders contaminating lymphoma cells of the autologous stem cell product the main source for disease recurrence. Clearing of these cells remains a prerequisite for curative stem-cell transplantation. Establishment of safe and effective therapeutic schedules using Mabs will enhance the chance for collection of lymphoma-free hematopoietic stems cells.

Purpose: Immune reconstitution was studied in 30 children who had received purged autologous bone marrow transplantation for neuroblastoma or acute myeloid leukemia (AML)., Methods: Patients with neuroblastoma received high-dose chemotherapy and total body irradiation, and patients with AML received chemotherapy alone. Marrows were purged ex vivo with either antineuroblastoma monoclonal antibodies (neuroblastoma) or 4-hydroperoxycyclophosphamide (AML). Lymphocyte subsets, mitogen stimulation studies, and immunoglobulin levels were studied every 4 months., Results: There were no significant differences between the two groups of patients in lymphocyte number or subsets over time. In both groups, CD2+ and CD4+ cells were below normal in 33% of patients at 12 months. CD4+/CD8+ ratios were below normal for up to 8 months after transplantation and natural killer cells were elevated for up to 2 years in most patients. Median IgG and IgA levels were below the age mean even at 2 years after transplantation, although patients with AML had significantly higher IgG levels at 12 months compared with those with neuroblastoma. Lymphocyte proliferative responses to mitogens were markedly reduced at 4 months but returned to normal at 8 months. Despite the delay in immune reconstitution, there were no life-threatening infections., Conclusions: There appeared to be little difference in the overall kinetics of immune reconstitution between the children with neuroblastoma, who received total body irradiation and high-dose chemotherapy, and those with AML, who received high-dose chemotherapy alone as their pretransplant preparative regimen.

Little information has been published concerning the severity of pain experienced by bone marrow donors or the use of local analgesia following bone marrow harvesting procedures. The aims of this study were to assess duration and severity of pain experienced by bone marrow donors and the effectiveness of bupivacaine as a local analgesic agent following bone marrow harvest. During a single blinded randomised study of 24 bone marrow donors, 10 ml of 0.5% bupivacaine was infiltrated either into the right or left posterior iliac crest of the donor immediately following bone marrow harvest. Donors were requested to record the level of pain experienced at the right and left harvest sites on a pain rating score sheet (0-10) at time intervals of 4, 8, 12, 24, 48 and 72 h following harvest. A significant reduction in pain was experienced at the harvest site infiltrated with bupivacaine when compared with the control site during the first 3 days post-harvest. It is recommended that bupivacaine be infiltrated routinely into the harvest sites of all bone marrow donors to reduce the pain experienced in the 3 days following harvest.

It has previously been reported that the use of mitobronitol (dibromomannitol, DBM) instead of busulphan (BU) for myelosuppression is associated with significantly decreased risk for several complications of allogeneic bone marrow transplantation in accelerated chronic granulocytic leukemia. In exploring the pharmacologic basis for this observation, we have compared the acute and subacute cytotoxicities of DBM and BU on the spleen and thymus of mice. While there was comparable early (day 3) weight loss in both organs following these treatments, splenic B cells exhibited significantly less damage, and thymic regeneration (over weeks) was significantly faster following DBM treatment than with BU. These observations raise the possibility that improved post-BMT immune recovery could contribute to the clinical benefits observed with DBM-preconditioning.

We report the case of a 24-year-old man who received high-dose cyclophosphamide (CY) 120 mg/kg over 2 days and twice daily fractionated total body irradiation (TBI) over 3 days(1,320 cGy) prior to allogeneic bone marrow transplantation. Seven and one-half years later he fathered a normal child who has developed normally so far.

Hematopoiesis after autologous bone marrow transplantation (BMT) is characterized by a prolonged and severe deficiency of marrow progenitors for several years, especially of erythroid and megakaryocyte progenitors, while the peripheral blood cells and marrow cellularity have reached relatively normal values within a few weeks. These anomalies are comparable to those reported for allogeneic BMT, despite the absence of any allo-immune reaction or post-graft immunosuppressive therapy. Post-graft hematopoietic impairment is the consequence of quantitative and qualitative changes involving both stem cell and stromal compartments which are expressed by an impaired capacity of stem cell self-renewal and commitment towards erythroid and megakaryocytic lineages. Besides the toxicity of conditioning regimens, hematopoietic reconstitution using autologous grafts is particularly dependent on a combination of factors related to the patient, such as underlying disease and pre-graft chemotherapy regimens, and to the graft processing itself, such as in vitro purging with chemotherapeutic agents.

Clonal chromosome aberrations observed in patients who have relapsed after autologous bone marrow transplantation (ABMT) are usually related to the cytogenetic abnormalities observed at diagnosis. In order to assess this relationship, we evaluated 30 acute non-lymphocytic leukemia (ANLL) patients who underwent ABMT at out institution and had evaluable serial cytogenetic studies before and after ABMT. Seventeen patients (57%) showed no chromosome aberrations after ABMT in any of the studies performed, while 13 patients (43%) carried abnormalities. In eight out of 30 patients (27%0 the abnormal karyotype after ABMT was associated with hematologic relapse. The cytogenetic abnormalities were: (1) the same as at diagnosis without additional abnormalities in five patients; (2) the same as at diagnosis but with additional abnormalities in three patients. In one patient a different karyotype from that of diagnosis was detected and a myelodysplastic syndrome was clinically evaluable. Furthermore, occasional and single cell chromosome abnormalities were observed in four patients (13%), none of whom relapsed. The new and additional clonal cytogenetic abnormalities observed after ABMT were found in eight patients (27%), suggesting that this event may not be so frequent, that is presumably associated regimen. The re-appearance of the chromosome aberrations after ABMT and the relationship with the risk of relapse are discussed.

Purpose: The use of in vitro purging of bone marrow in autologous bone marrow transplantation (ABMT) for non-Hodgkin's lymphoma (NHL) has been a controversial issue; its benefit is as yet unproven. Its effect on the clinical outcome of ABMT in these patients is still unclear. We look at this issue using data from the European Blood and Marrow Transplant (EBMT) Lymphoma Registry., Patients and Methods: Seventeen hundred twenty-six patients with NHL have been reported to the EBMT registry, of whom 270 had bone marrow purged at transplant. Two hundred twenty-four of these patients were compared with a case-matched group of 224 unpurged patients who had undergone the same procedure. The case matching was made following selection of the main prognostic factors for progression-free survival (PFS) by multivariate analysis. Response, complications, and outcome in ABMT were analyzed., Results: Time to hematologic engraftment, response to ABMT, and number of procedure-related deaths were similar in purged and unpurged patients. The overall survival (OS) rate was 54% at 5 years in purged patients and 48.3% in unpurged patients (P = .1813). The PFS rate was 44.3% and 44.6%, respectively (P = .1961). Patterns of relapse, including bone marrow relapse, were similar in both groups. Patients with low-grade lymphoma did not have a significantly improved PFS if the bone marrow was purged (P = .1757); however, they did have a significantly improved OS (P = .00184). This increased OS was found to be associated with non-totalbody irradiation (TBI) conditioning and also with the purged patients undergoing transplantation at large transplant centers (P = .0016)., Conclusion: Purging of bone marrow in ABMT for NHL does not affect the rate of hematologic engraftment or risk of procedure-related death (PRD). There is no significant difference in PFS for patients whose bone marrow is purged as compared with unpurged.

Cancer treatments often induce oral complications. In this study we investigate longitudinally the salivary gland function, the salivary caries-related microorganisms, and buffer capacity in bone marrow recipients. Stimulated saliva samples were taken midmorning. The salivary factors were studied in 42 patients from before transplant until 4 months after transplant. A dramatic reduction (66%) of salivary flow rate is noticed in all patients at 1 month after transplant, and only a partial recovery (42% reduction) is seen after 4 months. A clear shift toward a lower buffer capacity and a higher amount of cariogenic microorganisms is seen posttransplant. This shift is more pronounced when total body irradiation was included in the pretransplant conditioning therapy. These findings indicate that the studied parameters in transplant recipients can contribute to a higher caries risk and oral complications during the early posttransplant period.

Purpose: A non-radiation-containing regimen of busulfan and cyclophosphamide (BU/CY) was evaluated for toxicity, relapse, and long-term survival in patients who received allogeneic bone marrow transplantation (BMT) for myelodysplasia (MDS)., Patients and Methods: Thirty-eight patients with MDS, including eight with therapy-related MDS, were prepared for BMT using BU/CY., Results: Fourteen patients remain in first remission 18 to 60 months posttransplant. Five patients relapsed after BMT, and four of these patients died. Eight additional patients died of acute or chronic graft-versus-host disease (GVHD), and 11 died of regimen-related toxicity, primarily systemic mycoses. Overall survival rate at 2 years was 45% (95% confidence interval [CI], 0.30 to 0.61), with a 24% probability of relapse (95% CI, 0.10 to 0.49). Regimen-related toxicity was manifested primarily as hepatic dysfunction in 72% of patients, with 16% developing overt venoocclusive disease (VOD)., Conclusion: Non-radiation-containing preparative regimens offer long-term survival in allogeneic BMT for MDS that is comparable to that of radiation-containing regimens, and are useful in patients with therapy-related MDS. Monitoring BU levels may reduce regimen-related mortality and improve survival.

The purpose of this study was to describe the incidence, onset, duration, severity, and other relevant characteristics of mucositis and pain in patients undergoing bone marrow transplant (BMT) who were receiving high-dose chemotherapy (cytoxan, busulfan, and etoposide) without total body irradiation. A descriptive, longitudinal design was used to study a sequential sample of 47 patients undergoing allogeneic and autologous BMT. Each day, from 9 days prior to BMT through 21 days after BMT, nine anatomic regions of patients' mouths were assessed for extent and severity of mucositis. Oral pain was measured using the Short-Form McGill Pain Questionnaire. Forty-two patients (89%) developed mucositis, which, on average, began 3 days after transplant, lasted 9.5 days, and resolved by 12.6 days post-transplant. Thirty-six patients (86%) reported pain that began, on average, 4.5 days after transplant, lasted 6.5 days, and resolved by 11 days post-transplant. During the initial weeks following BMT, systematic assessment of the oral cavity areas that are at high risk for mucositis should assist nurses in detecting early oral complications and in initiating specific interventions. Additionally, attention needs to be given to the assessment and management of mucositis-related oral pain. Future nursing research should be conducted to examine efficient clinical methods of assessing mucositis and oral pain and to test prophylactic and therapeutic interventions.

Previously, we reported that 26 children with stage III or IV neuroblastoma (NBL) treated with BMT grew poorly post-BMT and significantly worse than a comparison group of hematologic BMT patients. Furthermore, unlike the hematologic patients, there was no apparent catch-up growth. Six of these previously reported long-term (> 2 years) NBL patients surviving BMT were evaluated with growth hormone (GH) provocative testing, frequent (every 20 min) overnight GH sampling and IGF-1 determinations. Three of 6 patients were GH deficient based on subnormal responses to provocative stimuli and subnormal pooled 12 h GH values. Only one child had completely normal GH testing and his growth was normal. Four patients were tested with recombinant GH for a period of 12-21 months. Three patients demonstrated an improvement in their growth velocity on therapy. However, the overall response to GH treatment was significantly less than the growth response in children who are GH-deficient due to causes other than BMT. In summary, GH deficiency may be a frequent complication of BMT treatment of NBL. It also appears that the BMT treatment protocol employing total body irradiation and high-dose melphalan may induce GH resistance.

Permanent alopecia after BMT has been reported as a side-effect associated with GVHD or after busulphan conditioning therapy, primarily in adults. We have reviewed children undergoing BMT to document the frequency of incomplete hair regrowth and to evaluate factors associated with this problem. Hair regrowth was studied in 74 children who survived > 6 months following BMT undertaken for malignant and non-malignant diseases. Alopecia was categorised as severe (< 50% of pre-transplant status), moderate (50-75%) or mild (> 75% but less than normal). Overall, 18 (24.3%) of 74 patients had mild (n = 5), moderate (n = 4) or severe (n = 9) alopecia. Risk factors for alopecia were presence of chronic GVHD (67%; p < 0.001), older age (p < 0.001) and prior cranial irradiation (42%; p = 0.03). Alopecia occurred in children receiving either busulphan (31%) or total body irradiation (16%; p = 0.15) as conditioning therapy. The highest frequency was seen in patients conditioned with busulphan with or without melphalan and who received prior cranial irradiation and/or developed chronic GVHD (75%). These data indicate that alopecia after BMT in children is a significant problem and confirm, in children, the previously noted association between alopecia and chronic GVHD and busulphan. Further risk factors of older age and prior cranial irradiation are identified. Consideration needs to be given to the use of an alternative to busulphan in children who are of older age, have received prior cranial irradiation and/or are at increased risk of GVHD.

The efficiency of stored platelet transfusion was evaluated in terms of clinical status in 136 thrombocytopenic patients. In a paired prospective study in which fresh platelets were used as controls, clinical efficiency was assessed on the basis of the ability to increase platelet count (recovery) and the interval to the next transfusion (D). In 48 clinically stable patients, recovery of fresh and stored platelets was similar (47% and 41% respectively) and the interval to the next transfusion was D4 and D3. In contrast, 27 patients who had bacterial infections showed significantly different recoveries (24%/5%) and the interval to the next transfusion was D3/D1 for fresh and stored platelets respectively. Similarly, in 16 patients who were treated concurrently with Amphotericin B, 18 other patients with graft-versus-host disease, 5 with splenomegaly and 3 with veno-occlusive disease (VOD), fresh platelets performed better than stored platelets, showing recoveries of 27%/18%, 29%/15%, 15%/1%, 22%/3%. Furthermore, the need for retransfusion within 24 hours was significantly increased with stored platelets. In 19 patients with anti-HLA allo-immunization who were transfused with HLA-matched fresh and stored APC, efficiency was similar (38%/36% and D4/D3). This study indicates that the storage has a major detrimental effect on platelet recovery and survival in patients with certain clinical conditions.

Based on encouraging results of a recently published study on the clinical usefulness of oral pentoxifylline (PTX) to reduce transplant-related toxicities, prophylactic pentoxifylline was administered to 31 consecutive allogeneic BMT recipients with hematological malignancies. Patients received PTX as a continuous infusion at increasing dose levels (0.50, 0.75, 1.00 and 1.25 mg/kg/h) starting 1 day prior to the conditioning regimen. At all dose levels, PTX was well tolerated with no significant side-effects. When compared with a historical control group of 61 consecutively transplanted allogeneic BMT recipients, PTX patients did not appear to experience less gastrointestinal (moderate and severe mucositis: 100% vs 68%, p < 0.001), hepatic (hyperbilirubinemia > 1.5 mg/dl: 84% vs 30%, p < 0.001) or renal (creatinine > 1.5 mg/dl: 16% vs 27%, NS) toxicity or to have a lower incidence of GVHD > or = grade III (21% vs 22%, NS). Using i.v. PTX, we were unable to reproduce the reduction in morbidity and mortality in patients undergoing BMT which has been described for prophylactic oral PTX.

One dose of pentostatin was added to a standard cyclophosphamide (CY) based transplant regimen in two patients in an attempt to decrease the rate of non-engraftment in haploidentical allogeneic BMT. Despite a normal cardiac history and evaluation prior to transplant, both patients suffered fatal cardiac toxicity within 48 h of receiving the chemotherapy. This phenomenon was further investigated in an animal model. Laboratory rats were treated with progressive doses of CY in a range that produces acute cardiac toxicity. Successive groups of rats were treated with either pentostatin or fludarabine and CY at 400 mg/kg. Neither pentostatin nor fludarabine alone produced early mortality. However, a marked increase in early mortality was noted in those animals treated with pentostatin and high-dose CY. The addition of fludarabine did not increase the early toxicity of CY. Autopsy revealed no gross or microscopic abnormalities in the animals. The implications of adding agents that interfere with adenosine metabolism to CY based transplant regimens is discussed.

The risks for the development of idiopathic pneumonia after allogeneic BMT were assessed in a case-series review at a single marrow transplantation center. All allogeneic marrow recipients (n = 299) (age range 1-60 years) with severe aplastic anemia (SAA) transplanted from family member donors after conditioning with CY were evaluated. Post-grafting immunosuppression consisted of MTX alone in 205 patients (69%), CY alone in 16 (5%) and a combination of the two in 78 (26%). The incidence estimate for any pneumonia within the first 200 days after transplant was 18% (95% confidence interval = 14-24%). Of 48 cases of pneumonia, CMV infection was documented in 44%, 21% were idiopathic and the remainder were either due to other infections or were not evaluated. The effect of acute GVHD on the incidence of pneumonia was examined using multivariate Cox proportional hazards models which included covariates for potential confounding factors. Consistent with previous reports, acute GVHD was associated with an increased incidence of any pneumonia (relative risk (RR) = 3.5, 95% Cl = 1.9-6.9; p < 0.001). Specifically, acute GVHD also was associated with the largest risk of idiopathic pneumonia (RR = 5.0, 95% Cl = 1.1-22; p = 0.04). In conclusion, recognition of acute GVHD as a risk factor for idiopathic pneumonia suggests that mechanisms in addition to chemoradiation damage are responsible for non-infectious lung injury after BMT.

Invasive fungal sinusitis is becoming increasingly common in patients undergoing BMT. This study was undertaken to evaluate the incidence, presenting symptoms, diagnosis procedures, treatment and outcome of invasive fungal sinusitis. The study population comprised 423 consecutive BMT patients at Hadassah University Hospital from January 1986 to August 1992. Eleven patients (2.6%) developed invasive fungal sinusitis, 8 had underlying hematologic malignancies and 3 severe aplastic anemia (SAA). Median interval between BMT and fungal sinusitis was 22.5 days (range 2-106 days). Eight of 11 patients had protracted neutropenia (median 8 days with median neutrophil count at the time of fungal sinusitis diagnosis of 0.25 x 10(9)/l). Four patients developed GVHD before fungal sinusitis was diagnosed. Presenting symptoms were fever (100%), orbital swelling (63%), facial pain (54%) and nasal congestion (36%). In 8 patients Aspergillus species were isolated (A. flavus in 7, A. quadrilineatus in 1); in 1 patient Candida albicans was isolated and in the other 2 fungal elements were detected histologically (Fusarium and Mucor, respectively). Six of the patients underwent surgical debridement at diagnosis. Three received granulocyte transfusions. All patients received systemic amphotericin B (7 conventional and 4 amphotericin B colloidal dispersion (ABCD)). Only 2 of the 11 patients responded completely to therapy with a follow-up of 15 months. It appears that invasive fungal sinusitis is a potentially fatal complication in immunocompromised patients post-BMT. Current treatment approaches are largely ineffective and new methods of management of this serious problem are needed.

Eighty-eight patients who received single fraction total body irradiation (sfTBI) as part of their conditioning for allogeneic BMT have been evaluated for the risk of cataract formation. Thirty-eight (43%) have developed cataracts; 11 required surgery. With 9.5-13.6 years follow-up (median 10.7 years), all 12 recipients of unmanipulated marrow allografts have developed cataracts; the actuarial risk of needing surgery was 32 (+/- 18%, 95% confidence intervals (CI)). Ten of these 12 required high-dose steroids (prednisolone > 1 mg/kg/day) for the treatment of GVHD. Seventy-six patients received T cell-depleted allografts; 14 of 76 required post-transplant immunosuppression with high-dose steroids. With 1-9.4 years follow-up (median 5 years), the actuarial risk of cataract formation in T cell-depleted allograft recipients is 72% (+/- 52% CI), the actuarial risk for needing surgery is 20% (+/- 9% CI). Recipients of sfTBI and non-T cell-depleted allografts had a significantly greater risk of developing cataracts (p = 0.003, long rank test) and of needing surgery (p < 0.05, log rank test) than patients receiving T cell-depleted BM. Cataracts occurred more frequently in patients requiring post-transplant immunosuppression with steroids (relative risk 2.12, p < 0.01 log rank test).

The aim of this paper was to present the results of bone marrow harvest followed by cryopreservation in 22 children with various malignant diseases, and the clinical course of autologous bone marrow transplantation (ABMT) performed in 10 children (three with acute lymphoblastic leukemia (ALL), three with acute myeloblastic leukemia (AML) and four neuroblastoma stage IV (NB)). In 20/22 children the harvested bone marrow contained a sufficient number of granulocyte-macrophage-colonyforming units (GM-CFU) for later marrow reinfusion. Hematological reconstitution was obtained in all 10 children who underwent ABMT. No child died of toxicity. The median time to neutrophil count > 0.5 x 10(9)/l, thrombocyte count > 50 x 10(9)/l and to discharge from hospital were 34, 49 and 29 days respectively. Five children are alive with no evidence of active disease 11-21 months after ABMT. Five children have suffered relapse and have died. It was concluded that sufficient amounts of precursor bone marrow cells may be harvested in children during a pause in cystostatic therapy. The acute toxicity of ABMT in children with malignant diseases was only moderate.

The kinetics of hematological recovery after autologous marrow transplantation have been studied in 70 patients with acute leukemia (38 acute nonlymphoblastic leukemia [ANNL] and 32 acute lymphoblastic leukemia [ALL]). The incidence of graft failure in this group was 3.2%, and a persistent severe thrombocytopenia was observed in 24% of the cases. Variables influencing engraftment have been studied using univariate and multivariate statistical analysis. Analysis of the entire group showed a correlation between graft colony-forming unit granulocyte-macrophage (CFU-GM) content and granulocyte recovery (p < 0.001). Marrow purging was associated with a delayed engraftment (p < 0.001). In ANLL patients, we found that high cummulated AraC doses before marrow cryopreservation correlated with poor granulocyte recovery after marrow infusion (p < 0.002). Platelet recovery was essentially affected by age, with shorter thrombocytopenia periods in younger patients (p < 0.001). Finally, excluding autotransplants with purged marrows, ALL patients showed better platelet recoveries than ANLL patients (p < 0.005). These findings will be useful to evaluate the risk of delayed engraftment after autologous bone marrow transplantation (ABMT) in patients with acute leukemia.

Hepatic veno-occlusive disease (VOD) is a non-thrombotic obliteration of the lumina of small intrahepatic veins. VOD has been reported after exposure to a wide variety of pathogens. It has been suggested that the chemoradiotherapy used as the conditioning regimen for bone marrow transplant (BMT) is now the main cause of this disease. However, the pathogenesis of VOD after BMT is probably multifactorial. Endothelial injury of sinusoids and small hepatic veins is considered to be the initial event in genesis of VOD. This injury is followed by deposition of fibrin-related aggregates in the subendothelial zone. These aggregates, and the intramural entrapment of fluid and cellular debris, occlude progressively the hepatic venous outflow and generate a postsinusoidal intrahepatic hypertension. Clinically, VOD is characterized by jaundice, weight gain, ascites, painful hepatomegaly and platelet refractoriness developing early post transplant, although other posttransplant liver disturbances can produce a similar syndrome. VOD diagnosis is usually established by applying the clinical criteria proposed by the Seattle and Baltimore groups. When clinical diagnosis of VOD is uncertain, a transjugular liver study including a transvenous biopsy and measurement of the gradient between wedged and free hepatic venous pressure, is recommended in order to establish an accurate diagnosis. According to the literature data, the incidence of VOD ranges from 0 to 70% and its mortality from 20 to 50%. This very wide range is attributable to the different incidence of risk factors in the different series and to the differences in applying the diagnostic criteria.(ABSTRACT TRUNCATED AT 250 WORDS)

Purpose: Bone marrow transplantation usually entails the ablation of the recipient's immune system. The recovery of immunity post-marrow transplantation is a complex process dependent on a number of pre- and posttransplant factors. This knowledge has led to the development of novel approaches to supportive care of the patient, as well as to methods of augmenting immunity., Design: Hematopoietic growth factors are now used to speed neutrophil recovery. Certain lymphokines are being investigated for the enhancement of cell-mediated immunity, and gamma globulin preparations are used to support the deficiency in humoral immunity., Conclusions: This review summarizes the basic concepts of immune reconstitution posttransplant and discusses some of the therapeutic interventions that have been investigated. In addition, some general recommendations are offered regarding supportive care.

Allogeneic BMT has been shown to be a highly effective therapy for both AML and ALL. With the availability of unrelated donors, continuing advances in the development of new and more effective transplant regimens, and the identification of agents such as the hematopoietic growth factors, alprostadil, and pentoxifylline to decrease the regimen related toxicities, BMT will become a viable option for a greater number of adults with acute leukemia. The optimal timing for BMT will continue to evolve, but based upon the currently available information, patients age 55 or less with AML with a high probability of relapse based upon cytogenetic abnormalities should be considered for transplantation in first remission if a related or unrelated donor can be identified. For patients at low risk for relapse (e.g., age 25 or less who have received high-dose intensification), transplantation can be delayed until documentation of early relapse. For patients with Ph1+ ALL or t(4;11), transplantation in first remission should be considered if a suitable related or unrelated donor is identified. Adults with ALL without adverse prognostic characteristics should be considered for transplantation at relapse or in second remission.

In August 1988 we began a program in which multiple myeloma patients achieving < or = 10% marrow plasma cells and > or = 50% reduction in paraprotein levels after the VAD (vincristine, doxorubicin, dexamethasone) regimen underwent bone marrow harvest, ex vivo marrow purging with 4-hydroperoxycyclophosphamide (4-HC) and marrow cryopreservation. Conditioning with a regimen of high-dose busulfan (total dose 16 mg/kg), cyclophosphamide (120 mg/kg) and melphalan (90 mg/m2) (BU + CY + MEL) followed by autologous BMT was then carried out. Seventeen of the 24 patients who received VAD (71%, 95% confidence interval [CI] 49 to 87%) were eligible for bone marrow harvest. One patient was not harvested because of non-medical reasons; two patients who underwent marrow harvest had gross plasmacytosis present in biopsies performed intraoperatively and did not undergo BMT. Fourteen patients (58%, 95% CI 37 to 78%) received BU + CY + MEL and 4-HC-purged autologous BMT. The median time to recovery of 0.5 x 10(9)/l neutrophils was 19 days (range 14 to 26) while the last platelet transfusion was given on a median of day 32 (range 10 to 46) post-BMT in the evaluable patients. The major non-hematologic toxicity was hepatic; two patients in complete remission died of hepatic veno-occlusive disease. Another patient succumbed to fungal infection despite neutrophil recovery. The remaining 11 patients achieved responses (complete in six and partial in five) associated with a normal performance status.(ABSTRACT TRUNCATED AT 250 WORDS)

Fourteen S/S children with severe SCD were transplanted with marrow from HLA identical siblings. All developed frequent (> 4/y) vasoocclusive crises (VOC) and recurrent acute chest syndrome episodes (n:10), osteitis (n:3), osteonecrosis (n:3), strokes (n:3) or frequent massive deglobulisation (n:2). Two children undergone splenectomy, 2 were chelated and 2 had erythroid allo-immunization. Ethnic origins were from various countries in Africa (n:10), North-Africa (n:3) or West Indies (n:1). At BMT, they were 2y 3m to 14y 9m old (mean:8y 7m). Donors were AS (n:11) or AA (n:3). At first, various conditioning regimens were used consisting of busulfan (BU) plus Cyclophosphamide (CY) at different doses: CY:200 mg/kg (n:12) or 260 mg/kg (n:2); BU:14 mg/kg (n:1), 16 mg/kg (n:9), > 16 mg/kg (n:4); 1 patient received also TLI and one other antithymoglobulin (ATG): 20 mg/kg. GVHD prophylaxis was CSA alone (n:4) or CSA plus short-term MTX (n:10). Median follow-up was 23 months (8 m. to 48 m.). All patients had an engraftment (d13 to d32) with a stable total chimerism in 10/14 patients who are cured. In the 4 others, partial chimerism was observed: one patient had a early and progressive rejection of his graft but is doing very well (28 m. follow-up) without any manifestation of SCD, with a high stable 22% Hb F level. One patient developed an aplastic anaemia 15 m after BMT: a second BMT was achieved 21 m after the first one with engraftment and total chimerism. Two patients have a relatively stable partial chimerism with still undergoing CSA therapy (11 m. and 23 m. follow-up).(ABSTRACT TRUNCATED AT 250 WORDS)

Allogeneic bone marrow transplantation (BMT) for chronic myelogenous leukemia (CML) offers the only significant chance of cure for this disease. About 50% of patients transplanted in the 1980s appear to be cured and with subsequent advances, it is suggested that more patients transplanted in the 1990s will be cured. Cyclophosphamide (Cy) (120 mg/kg) followed by fractionated total body irradiation (TBI) (Cy2/TBI) has been usually employed in preparation for BMT. Alternative regimens of Busulfan (Bu) (16 mg/kg) and Cy (120 mg/kg) (Bu/Cy2) or Bu (16 mg/kg) and Cy (200 mg/kg) (Bu/Cy4) have more recently been employed. At least three studies of Bu/Cy2 or Bu/Cy4 have given encouraging results. Two ongoing randomized studies of Bu/Cy2 versus Cy2/TBI have shown no difference in the event free survival (EFS). In addition, two ongoing randomized studies of Bu/Cy4 versus Cy (200 mg/kg) plus TBI (Cy4/TBI) show no significant differences in EFS. It appears that Bu/Cy regimens are as effective as Cy/TBI regimens. The choice of one regimen over the other depends on matters other than therapeutic efficacy.