Hematopoietic cell transplantation for primary plasma cell leukemia: results from the Center for International Blood and Marrow Transplant Research.

There are limited data on hematopoietic cell transplantation (HCT) in primary plasma cell leukemia (pPCL), an aggressive plasma cell disorder. We report outcomes of 147 patients with pPCL receiving autologous (n=97) or allogeneic (n=50) HCT within 18 months after diagnosis between 1995 and 2006. Median age was 56 years and 48 years for autologous HCT and allogeneic HCT, respectively. Progression-free survival (PFS) at 3 years was 34% (95% confidence interval (CI), 23-46%) in the autologous group and 20% (95% CI, 10-34%) in the allogeneic group. Cumulative incidence of relapse at 3 years was 61% (95% CI, 48-72%) in the autologous group and 38% (95% CI, 25-53%) in the allogeneic group. Overall survival (OS) at 3 years was 64% (95% CI, 52-75%) in the autologous group and 39% (95% CI, 26-54%) in the allogeneic group. Non-relapse mortality (NRM) at 3 years was 5% (95% CI, 1-11%) in the autologous group and 41% (95% CI, 28-56%) in the allogeneic group. The encouraging OS after autologous HCT, establishes the safety and feasibility of this consolidative treatment option after initial induction therapy for pPCL. Allogeneic HCT, although associated with a significantly lower relapse rate, carries a much higher risk of NRM and no OS benefit.

In pursuit of the allo-immune response in multiple myeloma: where do we go from here?

AlloSCT is a potentially curative procedure for haematological malignancies and marrow failure syndromes. However, unlike leukaemia and lymphoproliferative disorders, AlloSCT has yet to find its place in the clinical management of patients with multiple myeloma. AlloSCT in multiple myeloma is associated with a high procedure-related mortality (TRM up to 35%) when full-intensity conditioning is used and only up to 36% of cases show long-term disease-free survival. The introduction of reduced intensity conditioning AlloSCT, more recently following an autologous SCT, has reduced the TRM to <20%, but there is an associated increased relapse risk. The use of donor lymphocyte infusions and novel biological agents (thalidomide, bortezomib), alone or together, can be effective in relapsed and even persistent disease post-AlloSCT. Thus, in pursuit of the putative graft-versus-myeloma effect, we need to consider the whole patient management pathway both preceding (depth of response to novel agents) and post-AlloSCT, to minimize the toxicity while harnessing the adoptive immunotherapy effect. This review sets out what we have learned to date from the clinical research studies in this area, examines concepts for improving the outcomes of AlloSCT and proposes a potential direction of clinical investigation to maximize the effect of AlloSCT in multiple myeloma.

The assessment and management of adult patients with epilepsy--the role of general practitioners and the specialist services.

Recommendations have been made that all patients developing seizures should be referred to specialist services for full investigation and assessment and re-referred for issues such as inadequate seizure control, consideration of drug withdrawal and for pre-conceptual counselling. Bristol area general practitioners (GPs) were sent a questionnaire to determine their referral practices for adult patients with epilepsy. Details of their current management of these patients and their requirements from the specialist services were also obtained. Questionnaires were completed and returned by 67.8% of the GPs. Most referred their patients to the neurological or neuropsychiatric services. More than 70% wanted their new patients to be assessed within 4 weeks. Approximately, half at least sometimes treated their patients before this assessment of which a third never or only rarely sought advice as to the most suitable anticonvulsant. Most (71.5%) believed they had consultations with their patients with epilepsy at least yearly; however, only 34.3% had a recall system for non-attendees. Two-thirds either currently audited their practices or were willing to consider doing so, and 64.4% recognized a need for regular seminars on epilepsy. Few welcomed the introduction of joint clinics but two thirds believed co-operation cards could be useful. GPs in practices with an epilepsy nurse specialist were more supportive of the use of co-operation cards and were more likely to be involved in audit. Recommendations to improve the care provided by the Primary Health Care teams and aid communications with the specialist epilepsy services are made.

The clinical features, risk factors and outcome of thrombotic thrombocytopenic purpura occurring after bone marrow transplantation.

In this study, we retrospectively analysed the clinical features, risk factors and outcome of 22 patients with thrombotic thrombocytopenic purpura (TTP) occurring after allogeneic stem cell transplantation. All but two of these patients received stem cells from unrelated donors (UDs), two-thirds were female, three-quarters were adults and leukaemia was the major reason for transplant. The incidence of TTP was 20 out of 332 patients (6%) with UD transplants and two out of 104 recipients (2%) of matched sibling allografts (P = 0.16). In order to ascertain basic demographic risk factors for the development of TTP, we compared the 22 patients with 434 patients who did not develop TTP. Compared with patients who did not develop TTP, patients with TTP were nearly three times older (P < 0.001) and were more than twice as likely to be female (P = 0.001). Because > 90% of patients were recipients of UD marrow, we then compared the 20 UD-bone marrow transplantation (BMT) patients with 60 randomly selected UD-BMT patients who did not develop TTP. On univariate analysis, age and female gender were again significant risk factors, as was grade II-IV acute graft-versus-host disease (GvHD) (P = 0.002), and there was a trend towards an association with chronic GvHD (P = 0.083). However, after logistic regression analysis, only age and sex remained significant (P < 0.001 and 0.009 respectively). We report an 86% mortality with only three survivors out of 22 patients, and one of these remains thrombocytopenic and red cell transfusion dependent, possibly in part because of graft hypoplasia. Six out of 17 patients responded to plasmapheresis, but the majority of them ultimately succumbed because of TTP, often in association with GvHD or fungal infection.

T cell-depleted unrelated donor bone marrow transplantation for acute myeloid leukemia.

The outcome for 39 patients with acute myeloid leukemia (AML) in remission who had CAMPATH 1M T cell-depleted unrelated donor bone marrow transplantations (BMTs) is described. Conditioning was mainly with cyclophosphamide (120 mg/kg) and total body irradiation (TBI) (14.4 Gy), but 5 patients received busulfan in place of TBI and 200 mg/kg cyclophosphamide. All patients received cyclosporin, and short-course methotrexate was given to recipients of mismatched grafts. The patient population was predominantly pediatric (median age, 10 years), but one third of the patients was aged 15 years or above. Twenty-five patients were in second complete remission (CR2), and 14 had high-risk CR1 disease (primarily failed remission induction or antecedent myelodysplastic syndrome, often with complex cytogenetic abnormalities). Both recipient and donor were cytomegalovirus seronegative in 15 of 37 cases (38%); 51% of patients were matched for HLA class I and II. Grade II to IV acute graft-versus-host disease (GVHD) occurred in 24% of patients; chronic GVHD occurred in 5 of 31 evaluable patients (16%), 4 extensive and 1 limited. Relapse occurred in 5 cases (13%); 1 of these 5 patients survives, 24 months after a second unrelated donor transplantation. Two of these relapses were associated with secondary graft failure (incidence rate, 5%). All patients engrafted primarily. Severe viral infection was the major transplant-associated complication, with 12 episodes in 9 patients, 5 of them lethal. Twenty-five patients survive at a median follow-up of 44 months (range, 2-102 months), with estimated actuarial overall and disease-free survival rates at 44 months of 61% (SE 8%) and 57% (SE 8%), respectively. Nineteen patients are more than 2 years post-BMT and may be cured. The functional status of long-term survivors is excellent, with 19 of 21 patients who survive 6 months or more in full-time employment or full-time students. These encouraging results suggest that in patients lacking a sibling donor, unrelated donor BMT for AML in remission achieves survival figures as good as or better than those reported on patients with autologous stem cell transplantation, and that T-cell depletion of grafts is associated with a low relapse rate and an excellent functional status. However, only a randomized study comparing unrelated donor BMT and auto-grafting will resolve which of these treatment strategies is better for patients with AML.

An analysis of neuropsychological change scores following selective temporal resection of the non-dominant temporal lobe.

Reliable change in neuropsychological test scores was examined in patients undergoing right-sided, selective temporal resections for the relief of intractable epilepsy. Measures were taken prior to surgery, 1-month post-operatively and 1-year post-operatively. Non-verbal memory performance was more robustly measured than in previous studies. Results failed to replicate previous studies which report verbal memory deficits even following right-sided surgery. No strong evidence of a material-specific, non-verbal memory deficit was found on commonly used tests of non-verbal memory. The majority of patients failed to show reliable decline in performance following surgery indicating that fears of post-operative memory decline may be unfounded.

A quality of life study in 20 adult long-term survivors of unrelated donor bone marrow transplantation.

There are few specific data available concerning quality of life (QOL) of survivors of unrelated donor bone marrow transplantation (UD-BMT). The procedure is expensive, difficult and is being employed increasingly yet we have little information concerning the QOL of survivors to justify this intervention. In this study, 20 long-term (>1 year post-BMT) survivors were studied with four self report questionnaires designed to assess quality of life, satisfaction with life, social support and employment status. Overall, satisfaction with life measures was above average but there was dissatisfaction with physical strength and appearance. The post-transplant employment data indicates that 60% of long-term survivors returned to full-time work and 15% to part-time work. Failure to return to work was not correlated with graft-versus-host disease (GVHD), relapse, age at or time since transplant. In general, there was a good correlation between the clinician's and patient's view of their health but the clinician's assessment of the patients mental health and energy was higher than the patients reported. Further research is required in the area of QOL post-UD-BMT. This will enable transplant physicians to counsel patients better pre-BMT and to evaluate fully the results achieved by different centres performing the procedure.

Unrelated donor bone marrow transplantation in adults: some current controversies.

The results of unrelated donor bone marrow transplantation are continually improving. These improved results are due to a better understanding of the complications of the procedure and the devising of strategies to avoid them. Nonetheless, many problems remain. This review will address some of the major controversies of the field including the indications for UD-BMT, infection, GVHD prophylaxis and treatment and whether UD-BMT should only be performed in specialist centres. Conclusions will be supported by evidence from the limited published literature and the authors' experience in 3 major transplant centres.

Unrelated donor bone marrow transplantation for children and adolescents with Philadelphia-positive acute lymphoblastic leukemia.

PURPOSE: Few patients with Philadelphia-positive acute lymphoblastic leukemia (Ph-positive ALL) have been cured by chemotherapy alone. Registry figures show that 38% of patients who have a matched-sibling bone marrow transplant (BMT) are disease-free 2 years after transplant, but the majority of patients lack a sibling donor. Most modern ALL protocols recommend unrelated donor (UD) BMT for patients with Ph-positive ALL in first complete remission (CR1), but the outcome of this is unknown. PATIENTS AND METHODS: We report the results of 15 children and adolescents who had a T-cell depleted UD-BMT for Ph-positive ALL. Thirteen of 15 had been previously treated on United Kingdom ALL protocols. Nine were in CR1 and six had more advanced disease. Eleven donor recipient pairs were matched at HLA-A, HLA-B, HLA-DR, and HLA-DQ, and four were mismatched at one or two HLA loci. RESULTS: The incidence of greater than grade I acute and chronic graft-versus-host disease (GVHD) was low (13% and 8%, respectively). Six patients have relapsed and seven patients survive at a median of 21 months post-BMT; six of seven are disease free. All seven survivors are in full-time education or work. The 2-year overall and disease-free survivals are 44% +/- 13% and 37% +/- 13% (+/- SE). None of four patients who had mismatched donors survived, but seven of 11 matched recipients survive (P < .05). CONCLUSION: UD-BMT can produce prolonged disease-free survival in young patients with Ph-positive ALL who otherwise would have an extremely poor outlook.

Obstructive sleep apnoea following rapid weight gain secondary to treatment with vigabatrin (Sabril).

A case of a patient with medically intractable epilepsy, who developed obstructive sleep apnoea (OSA), and an increase in seizure frequency, as a consequence of weight gain following treatment with vigabatrin is described. The relationship between exacerbation of epilepsy and sleep disruption secondary to OSA is discussed. Recommendations regarding the choice of anticonvulsants in patients at risk of developing OSA are made.

A randomized study of VAD therapy with either concurrent or maintenance interferon in patients with newly diagnosed multiple myeloma.

This randomized study was designed to determine whether response to VAD chemotherapy could be prolonged by using rh alpha-2b-interferon (IFN) at a dose of 3 mU three times per week, either concurrently with VAD (VIC) or as maintenance after completion of VAD (VIF). Maintenance IFN was given for 9 months in order for the duration of IFN therapy to be similar in both groups. 72 patients were randomized between December 1988 and August 1993. The majority of patients had poor prognostic features. The objective response rate was similar in each arm, 78% in VIF and 77% in VIC. Of the 56 responders, 33 have relapsed, three died in remission, and 18 proceeded to high-dose therapy, withdrew for other reasons or were lost to follow-up and were censored from analysis at the relevant time point. Only two patients remain in remission (both in partial remission). Median PFS was 15 months for both VIF and VIC, compared with 16.5 months for a historic control group treated with VAD alone (n.s.). The estimated median survival in VIF was 43 months and in VIC 22 months, compared with 45 months in the historic controls (n.s.). These findings indicate that neither maintenance nor concurrent IFN prolongs response to VAD.

4-Hydroperoxycyclophosphamide purged autologous bone marrow transplantation in non-Hodgkin's lymphoma patients at high risk of bone marrow involvement.

Between June 1990 and January 1994, 19 patients with non-Hodgkin's lymphoma (NHL) at high risk for bone marrow involvement underwent 4-hydroperoxycyclophosphamide (4-HC) purged bone marrow transplantation. Eleven patients had low grade, seven intermediate grade and one high grade NHL and 7/19 patients had received three or more previous chemotherapeutic regimens. Four patients were transplanted in first partial remission (PR) and the remainder in responsive relapse. Fourteen patients had bone marrow (BM) involvement at diagnosis and/or at relapse. The median times to granulocyte and platelet recovery were 26 and 29 days, respectively. There were two toxic deaths and one complete responder developed secondary AML at 31 months post-BMT. Seventeen of 18 evaluable patients achieved a complete remission (CR) and one patient a PR. Fourteen patients (74%) are progression-free at a median follow-up of survivors of 34 months (range 29-55). The 3 year event-free (EFS) and overall survival (OS) probabilities are both 67%. No statistically significant difference was seen between EFS or OS and BM involvement or histologic grade at diagnosis. At 29 months, 4/7 patients with a morphologically involved BM harvest had relapsed or died compared to 1/12 patients with negative BM (P = 0.03). These results are encouraging and warrant further investigation of 4-HC purging in NHL.

Autologous stem cell transplantation in multiple myeloma: results of the European Group for Bone Marrow Transplantation.

Autologous hematopoietic stem cell transplantation was used for treatment of 384 patients with multiple myeloma in 37 centers during the years 1986-1994. An analysis of prognostic factors was performed in 207 of these patients. One hundred forty one were males and 66 females, and median age was 49 years (range, 24-68). Actuarial survival at 78 months is 45%. Factors associated with a good prognosis were: response on chemotherapy immediately pretransplant, administration of only one treatment regimen, a low serum-beta 2-Microglobulin value at diagnosis and the use of a conditioning regimen including melphalan. In a multivariate analysis, response status pretransplant, age < 45 years, melphalan conditioning and non-TBI conditioning were independently predictive for longer survival, while transplantation after only one line of primary treatment and isotype other than light-chain were of borderline significance. Post-transplant alpha-interferon treatment was associated with improved survival in responsive patients. Eighteen patients treated in one center (Huddinge) passed a double autograft program, and 14 are in continuous complete remission ([CR]; n = 10) or good partial remission (n = 4) at a median time of 17 months after the first transplant (range, 2-38). In five CR patients, polymerase chain reaction (PCR)-analysis of the clone-specific immunoglobulin-rearrangement was performed, and four are PCR-negative up to 33+ months after the first transplantation. We conclude that autografting in myeloma is most effective when applied early in the course of disease in younger, chemotherapy-reponsive patients. Alpha-interferon maintaince treatment seems to be beneficial with respect to improved survival.(ABSTRACT TRUNCATED AT 250 WORDS)

Double high-dose chemoradiotherapy with autologous stem cell transplantation can induce molecular remissions in multiple myeloma.

Fifteen patients with stage II-III multiple myeloma were intended to undergo two sequential cycles of myeloablative chemoradiotherapy with autologous bone marrow or blood stem cell transplantation after response to primary induction chemotherapy. BM grafts were used in 13 of the 15 first transplants whereas PBSC were used for the two remaining first transplants and all second transplants. The preparative regimen was melphalan 200 mg/m2 for the first transplant and melphalan 140 mg/m2 plus total body irradiation (TBI) 10 Gy for the second. Before the first transplant, 12 patients were in PR and three in CR whereas seven were in CR and seven in PR after the first transplantation. Four patients received only one cycle of myeloablative therapy because of incomplete hematopoietic reconstitution after transplantation (three patients) and early death (one patient). Eleven patients proceeded to the second transplant, and six patients were then in CR and five in PR. After the second transplant a further two patients entered CR whereas three remained in PR. Of all 15 patients, 11 remain in continuous complete (eight patients) or partial (3 patients) remission at a mean time of 20 months after the first transplant. Five patients in CR were examined by PCR analysis of the clone-specific immunoglobulin gene rearrangement for detection of minimal residual disease and four of these are PCR-negative up to 33 months after the first transplant. One transplant-related death occurred, and one patient died from progressive disease. This superintensive treatment regimen for younger patients with multiple myeloma has acceptable toxicity, and can induce and sustain long-term complete remissions.

Molecular detection of clonally rearranged cells in peripheral blood progenitor cell harvests from multiple myeloma patients.

Peripheral blood progenitor cells (PBPC) are increasingly used for autologous reconstitution following high-dose chemotherapy in multiple myeloma but it is unclear whether these cells are less likely to be contaminated with malignant cells than bone marrow (BM). We have investigated this using immunoglobulin heavy-chain (IgH) gene fingerprinting, a polymerase chain reaction based technique with a sensitivity of 0.1-0.01% (10(-3)-10(-4)). We have looked for patient-specific IgH rearrangements in leukapheresis samples from eight myeloma patients undergoing PBPC harvest. Seven were in first remission (six partial, one complete) and one in second complete remission. Mobilization of PBPC was accomplished using cyclophosphamide (4 or 7 mg/m2) and rhG- or GM-CSF. Between two and five leukaphereses were performed in each patient. Patient-specific IgH rearrangements were identified in diagnostic BM in all patients and bands of identical size were found in one or more leukaphereses from 6/8 patients. Overall, 14/32 leukaphereses were shown to be contaminated. Two patients who showed contamination of at least one PBPC harvest had BM harvests in which contaminating cells were not detectable, suggesting that PBPC are not necessarily less likely to be contaminated than marrow stem cells. These results indicate that PBPC harvests from the majority of myeloma patients are likely to contain contaminating cells. Further studies are needed to determine whether these cells are clonogenic and whether they contribute to relapse.

Minimal residual disease after bone marrow transplantation for multiple myeloma: evidence for cure in long-term survivors.

Allogeneic bone marrow transplantation (BMT) can induce long-term complete remission (CR) in patients with multiple myeloma but it is not yet clear whether the disease can be eradicated. We have used immunoglobulin gene fingerprinting, a PCR-based technique, to evaluate minimal residual disease in 5 patients in unmaintained CR 9-60 months after allogeneic BMT. All 5 patients were PCR-positive within the first year after BMT, suggesting that early PCR positivity is common and not predictive of relapse. Three patients were studied at > 1 year post-transplant; one had become PCR-negative at 1 year, a second at 2 years and the third at 4.5 years post-BMT. The ability of the technique to detect clonal evolution was demonstrated by serial studies in a further patient who relapsed post-BMT. The absence of any detectable disease at the molecular level in 3 patients in long-term CR post-transplant suggests that cure of multiple myeloma may be a realistic goal.