Parental distress and catastrophic thoughts about child pain: implications for parental protective behavior in the context of child leukemia-related medical procedures.

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.

Therapy-related Ph+ leukemia after both bone marrow and mesenchymal stem cell transplantation for hypophosphatasia.

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.

Non-myeloablative allogeneic hematopoietic stem cell transplantation.

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.

Purging of peripheral blood stem cell transplants in AML: a predictive model based on minimal residual disease burden.

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.

An update on the role of high-dose therapy with autologous or allogeneic stem cell transplantation in mantle cell lymphoma.

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.

Is it safe to treat allogeneic stem cell transplanted recipients at home during the pancytopenic phase? A pilot trial.

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.

Outpatient management of autologous haematopoietic cell transplantation: the Barcelona experience.

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.

High incidence of neutropenia in patients treated with rituximab after autologous stem cell transplantation.

We report a high incidence of neutropenia in patients treated with rituximab prior to and following autologous stem cell transplantation (ASCT). Fourteen patients with follicular or mantle-cell lymphoma were treated with high dose (HD) therapy followed by an in vivo-purged autologous graft.

Efficacy and toxicity of a virus-directed enzyme prodrug therapy purging method: preclinical assessment and application to bone marrow samples from neuroblastoma patients.

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.

Oral complications associated with the treatment of pediatric neuroblastoma: a case study.

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.

Art therapy as support for children with leukemia during painful procedures.

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.

Allogeneic hematopoietic cell transplantation without myeloablative conditioning for patients with advanced hematologic malignancies.

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.

Cytomegalovirus colitis after autologous transplantation for multiple myeloma.

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 after CD34+-purified autologous peripheral blood progenitor cell 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.

Permanent alopecia following chemotherapy and bone marrow transplantation.

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.

Immune reconstitution after autologous purged bone marrow transplantation in children.

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.

In vitro and in vivo purging of B lymphoma cells from stem-cell products using anti-CD20 Abs.

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.