Ar Perry

Back-up bone marrow is frequently ineffective in patients with poor peripheral-blood stem-cell mobilization.

PURPOSE To assess hematologic recovery and procedure-related mortality in patients who received high-dose therapy with stem-cell support, in whom the peripheral-blood stem-cell (PBSC) collection fails (CD34+ cells < 1 x 10(6)/kg). The predictive value of granulocyte-monocyte colony-forming cell (GM-CFC) measurements and the value of bone marrow obtained after PBSC collection failure was assessed. PATIENTS AND METHODS The study group comprised 324 consecutive patients mobilized with granulocyte colony-stimulating factor (G-CSF) and cyclophosphamide (273 patients), G-CSF with other chemotherapy (37 patients), and G-CSF alone (14 patients). Between one and four aphereses were performed. RESULTS In 51 of 324 patients, there was failure to obtain 1 x 10(6)/kg CD34+ cells. Twenty-three patients had greater than 1 x 10(5)/kg GM-CFC; 22 patients proceeded to high-dose therapy. Neutrophil recovery occurred within 21 days, but platelet independence was delayed (> 28 days) in eight patients. Of 28 patients with less than 1 x 10(5)/kg GM-CFC, six received high-dose therapy with PBSC alone and five had delayed engraftment. Twelve patients with less than 1 x 10(5)/kg GM-CFC received high-dose therapy supported by bone marrow collected after PBSC collection failure. Eleven patients were assessable for engraftment; four patients had slow (> 21 days) or delayed (> 28 days) neutrophil recovery and eight patients had delayed platelet recovery. In the group of patients who received less than 1 x 10(5)/kg GM-CFC, there were five procedure-related deaths. CONCLUSION This study shows that delayed hematologic recovery is frequent if less than 1 x 10(6)/kg CD34+ cells are infused after high-dose therapy, particularly with GM-CFC less than 1 x 10(5)/kg. The procedure-related mortality in this latter group is high. In most patients whose PBSC collection contains less than 1 x 10(5)/kg GM-CFC, the use of bone marrow cells does not improve engraftment, which suggests that poor PBSC mobilization usually indicates poor marrow function.

Progenitor cell yields are frequently poor in patients with histologically indolent lymphomas especially when mobilized within 6 months of previous chemotherapy.

High-dose therapy with peripheral blood stem cell (PBSC) support is a frequently used treatment option in younger patients with poor prognosis histologically indolent (low-grade) non-Hodgkin’s lymphoma (NHL), usually at the time of second or subsequent response to conventional-dose therapy. We have undertaken PBSC collection in 57 patients with histologically indolent NHL mobilized with either cyclophosphamide 1.5 g/m2 or the ESHAP regimen, followed by daily G-CSF. Progenitor cell yields were determined by quantification of CD34+ cells and GM-CFC. Twelve patients (21%) failed to achieve the minimum progenitor cell requirements of 1 × 106/kg CD34+ cells or 1 × 105/kg GM-CFC in their pooled harvests and 40 patients (70%) failed to achieve the optimal harvest thresholds of 3.5 × 106/kg CD34+ cells or 3.5 × 105/kg GM-CFC. This high failure rate is significantly higher than that in patients with histologically aggressive NHL or Hodgkin’s disease. A multivariate analysis was performed to identify factors contributing to the low stem cell yields in this group. This identified the time interval from the last chemotherapy to the priming chemotherapy as the most important predictive factor. With respect to CD34 and GM-CFC numbers, on the single harvest on the day the white cell count first exceeded 5 × 109/l the P values were 0.0078 and 0.0065, respectively, and for the progenitor cell values on the pooled harvests the P values were 0.004 for CD34+ cells and 0.015 for GM-CFC. Progenitor cell yields may therefore be improved in patients with low grade lymphoma by harvesting at diagnosis if no marrow disease is present, or by delaying mobilization for 6 months post-chemotherapy in patients in first or subsequent remission.

A case of EBV-associated lymphoproliferative disease following high-dose therapy and CD34-purified autologous peripheral blood progenitor cell transplantation.

A fatal case of EBV-associated lymphoproliferative disorder arising after a CD34-selected autologous peripheral blood stem cell transplant is reported in a patient with multiple myeloma in first plateau phase. It is suggested that this is likely to be a consequence of the accessory cell depletion associated with the CD34+ cell purification and it is recommended that a source of autologous T cells is stored before transplantation to be used if a severe opportunistic infection or EBV lymphoma arises post-transplantation.

Evaluation of clinical scale CD34+ cell purification: experience of 71 immunoaffinity column procedures.

Seventy-one mobilised PBSC collections were subject to CD34+ cell purification using the CEPRATE SC® stem cell concentration system. The overall median purity of CD34+ cells was 69% (6–93%). CD34+ cell, and GM-CFC recoveries were 52% (8–107%) and 36% (3–118%). Purity was logarithmically related to the input percentage of CD34+ cells and starting requirements were established of 1% CD34 cell content for optimal purity and a minimum of 2 × 106/kg CD34+ cells to ensure recovery of our minimum engraftment threshold of 1 × 106/kg CD34+ cells. Reduction of the washing steps reduced non-specific cell losses and shortened the procedure but did not affect progenitor cell recovery. Purified CD34+ cells were reinfused following high-dose therapy in 35 patients. The median time to neutrophil recovery of 0.5 × 109/l was 12 (10–23) days and to the attainment of platelet independence was 13 (7–100) days. The risks of delayed platelet recovery were related to the CD34+ cell dose infused and were identical to the risks when non-purified PBSC collections were used. In conclusion, purification of CD34+ cells using the CEPRATE device is reliable and the purified product results in prompt engraftment. The cell losses that occur do however restrict its use in many patients.

A fatal case of autoimmune thrombocytopenia with an IgM anti-GPIb/IX following one antigen mismatched unrelated donor bone marrow transplantation.

We report the case of a 32-year-old patient with ALL who developed autoimmune thrombocytopenia 2 months following allogeneic bone marrow transplantation. An IgM autoantibody against the platelet glycoprotein Ib/IX complex was observed. Treatment with high-dose steroids and intravenous immunoglobulin G failed to produce any benefit and the thrombocytopenia led to fatal gastrointestinal haemorrhage. The possible factors contributing to post-allograft thrombocytopenia and potential management strategies are discussed.

The history of bone-marrow transplantation.

As it influenced so much else this century, so the atomic bomb essentially marked the beginnings of interest in bone-marrow transplantation. The first detonation of a nuclear device in New Mexico in 1945, and the subsequent effects of the atomic bomb on the populations of Hiroslaima and Nagasaki provoked great and urgent interest in the effects of irradiation. While studying the effects of lethal irradiation in mice, Jacobson (1949)’ discovered a protective effect of splenic shielding: the spleen in mice contains haemopoietic tissue. He went on to demonstrate a similar protective effect by shielding the femur (1951).2 A year later, Lorenz showed that this protection could also be conferred by intravenous bonemarrow infusion.3 At first, it was thought that the radiation protection was due to humoral elements in the syngeneic bone marrow. Over the next five years, however, a number of investigators demonstrated that, not only was the protection due to cellular elements, but that these donor cells effectively repopulated the irradiated marrow.cw.“9 An animal whose haemopoietic system was derived from another animal was termed a ‘radiation chimera’.’ In 1958, a radiation accident occurred in Vinca, Yugoslavia, and six physicists developed radiationinduced aplasia. Although one died, Mathe” described the successful infusion of allogeneic bone marrow into the remaining five, and subsequently

Peripheral blood stem cell versus autologous bone marrow transplantation for Hodgkin's disease: equivalent survival outcome in a single-centre matched-pair analysis.

A matched‐pair retrospective analysis was used to compare 70 patients who had undergone peripheral blood stem cell transplantation (PBSCT) with 70 who had undergone autologous bone marrow transplantation (ABMT) for Hodgkins disease. All transplants took place at a single centre using the same conditioning regimen (BEAM). Patients were matched for sex, previous chemotherapy and relapse status: factors which have previously been shown to have prognostic significance for transplant outcome in Hodgkins disease at this centre. The two groups were also generally comparable for unmatched patient and disease characteristics. Toxic deaths and 90 d outcome were not different between the two groups. Three‐year overall survival was 68.6% for the ABMT group and 78.2% for the PBSCT group (P = 0.078); progression‐free survival was 59.4% for the ABMT group and 58.1% for the PBSCT group (P = 0.255), and relapse rates were 36.9% and 42.6% respectively (P = 0.30). Within the limitations of retrospective analysis, we conclude that there is no major overall or progression‐free survival advantage for PBSCT compared to ABMT in Hodgkins disease.

Bone Marrow Transplant Patients With Life-Threatening Organ Failure: When Should Treatment Stop?

PURPOSE To discuss issues surrounding life support in bone marrow transplant (BMT) patients, issues that may determine how far we go to keep a deteriorating BMT patient alive--and when we stop trying. How can we define survival chance in BMT patients, and when should prolongation of life be deemed inappropriate? Who should make the decision to terminate support? And how should life support be terminated? DESIGN Prognostic factors that predict for almost certain nonsurvival have been identified in BMT patients with life-threatening organ failure. The concept of futility raises the question of how low the chance of survival must be before termination of life support is justified--but the concept is flawed, and the value judgments involved in decision making must also be considered. Then, once a decision is made, the manner of withholding or withdrawing life support is also open to discussion. CONCLUSION Despite controversies, there are areas in which improvements to current practice might be considered. More data are required to determine survival chances of BMT patients with life-threatening organ failure. Greater attention might be devoted, in pretransplant counseling, to issues of intensive life support, with the patients own views being ascertained before transplantation. And, because technologic possibilities are now imposing fewer boundaries, the problem of finite resources may need to be readdressed, with treatment limits being set down before transplantation.

Early PCR-negativity after allogeneic BMT in adults with t(4;11) ALL in the absence of acute or chronic GVHD

Acute lymphoblastic leukaemia (ALL) with the t(4;11) translocation has a very poor prognosis following conventional chemotherapy. Many patients are offered an allogeneic BMT in first remission. We report on the impact of allogeneic BMT on three patients with t(4;11) ALL in first remission. Median age was 20 years. One patient received marrow from an HLA-identical sibling and the other two from unrelated donors. All three engrafted and none of the patients developed acute or chronic GVHD. Remission status was monitored using a sensitive nested RT-PCR to detect the ALL-1/AF-4 hybrid transcript. All three were PCR-negative at 3 months post-BMT. One of the unrelated recipients died of a fungal infection 4 months post-BMT. The other two are alive and in molecular remission at 21 and 24 months post-BMT. This is the first report of longitudinal follow-up of t(4;11) ALL post-allogeneic BMT by PCR. The early attainment of molecular remission in the absence of GVHD suggests that the conditioning regimen may have been more important than a graft-versus-leukaemia effect in these patients. Follow-up of larger numbers of patients will be required to confirm these preliminary observations.