Søren L. Petersen

Cerebral and meningeal multiple myeloma after autologous stem cell transplantation. A case report and review of the literature

Meningeal involvement of multiple myeloma is a very rare complication. Defining meningeal myelomatosis (MeM) as the presence of plasma cells in the cerebrospinal fluid in a patient with multiple myeloma, we have found 53 previously reported cases in the literature, where the diagnosis MeM has been made while the patient was alive. Using Kaplan Meier statistics we have found the median survival, from the time of diagnosis of MeM, to be 1.5 months. We report a case with MeM and possible cerebral myeloma shortly after autologous stem cell transplantation, and compare it with earlier published cases. Am. J. Hematol. 62:228–233, 1999.

Haematopoietic stem cell transplantation with non‐myeloablative conditioning in the outpatient setting: results, complications and admission requirements in a single institution

Thirty patients with haematological malignancies received peripheral blood stem cells from human leucocyte antigen (HLA)‐identical sibling donors after non‐myeloablative conditioning with fludarabine and total body irradiation. Twenty‐seven patients received the transplant as an outpatient procedure. All patients engrafted. The probability of acute graft‐versus‐host disease (GVHD) grades II–IV and extensive chronic GVHD was 57% and 80%, respectively. Patients alive on day +365 experienced a median of 44 d (range 4–151) of hospitalization during the first year. In the entire cohort, GVHD accounted for 22%, infections for 18%, thrombotic thrombocytopenic purpura (TTP) for 16% and engraftment syndrome for 14% of the time in hospital. The 1‐year risk of TTP was 26%. Acute GVHD was a risk factor for the development of TTP (P = 0·008). With a median follow‐up of 602 d, the 2‐year estimates for overall survival, progression‐free survival, non‐relapse mortality and relapse related mortality were 68%, 43%, 22% and 13%, respectively. This transplantation regimen is feasible and induces long‐term remissions in heavily pretreated patients. The procedure can be performed in the outpatient setting, but complications could result in a substantial number of admissions during the first year.

Evidence for involvement of clonally expanded CD8 + T cells in anticancer immune responses in CLL patients following nonmyeloablative conditioning and hematopoietic cell transplantation

We have analyzed the clonotype composition of CD8+ T cells following nonmyeloablative (NMA) conditioning and hematopoietic cell transplantation (HCT), of patients with chronic lymphocytic leukemia (CLL). Consecutive analyses of blood samples taken up to 2 years following HCT, demonstrated that CD8+ T-cell clonality was highly dynamic in the early phases after HCT, but became more stable after 4–5 months. Moreover, donor lymphocyte infusion (DLI) given for disease progression in one of the patients led to establishment of recurrent as well as new T-cell clonotypes. This coincided with disease remission, strongly suggesting that these T cells were engaged with anti-CLL cytotoxicity. To examine the functional capacity of stable clonally expanded T cells after HCT, CD8+ T cells isolated post-transplant from the recipients were stimulated ex vivo with CLL cells and subsequently analyzed by FACS for surface expression of the marker for cytotoxic activity, CD107a. Stimulation with CLL cells indeed led to surface expression of CD107a, and clonotype analyses of sorted cells demonstrated that CD107a positive T cells were stably expanded following HCT. Our data suggest that clonally expanded CD8+ T-cell clones participate in the ongoing T-cell response against CLL cells following HCT with NMA conditioning.

Graft rejection after hematopoietic cell transplantation with nonmyeloablative conditioning

Graft rejection after hematopoietic cell transplantation (HCT) with nonmyeloablative conditioning is a rare but serious clinical problem. Graft rejection and salvage therapy in eight patients in a retrospective analysis of 124 consecutive patients is reported. The patients were conditioned with low‐dose fludarabine and total body irradiation (TBI). The association of pretransplantation risk factors with rejection and the effect of chimerism and graft‐versus‐host disease on rejection were analyzed. Overall survival (OS) and progression free survival (PFS) were compared between patients with and without rejection. Retransplantation was performed with increased TBI conditioning for all patients, and with increased mycophenolate mofetil doses for recipients with HLA‐identical sibling donors. No known pretransplantation risk factors were confirmed in this study. Rejection episodes were unevenly distributed over time. The storage temperature of the apheresis products was identified as a risk factor for rejection. Storage of the apheresis products at 5°C diminished the risk of rejection. Low donor T cell chimerism at Day +14 significantly increased the risk of rejection. Seven patients were retransplanted. All but one engrafted successfully, but with decreased OS and PFS. Two patients received pentostatin infusion prior to donor lymphocyte infusions in unsuccessful attempts at reversing rejection. Storage temperature and donor chimerism had a significant effect on rejection. Following rejection, patients are at greater risk of dying from infections and progression/relapse of their malignancy. Retransplantation is feasible and well tolerated after HCT with nonmyeloablative conditioning and should be performed without delay in patients with imminent and manifest graft rejection. Am. J. Hematol. 2008.

Single‐institution long‐term outcomes for patients receiving nonmyeloablative conditioning hematopoeitic cell transplantation for chronic lymphocytic leukemia and follicular lymphoma

Non‐myeloablative conditioning hematopoietic cell transplantation (NMC‐HCT) has improved the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL). In a cohort of 85 patients (45 with CLL and 40 with FL), we observed 5‐yr overall survival (OS) and progression‐free survival (PFS) of 53% and 38% in the CLL group and 81% and 76% in the FL group. In the both the CLL group and the FL group, a strong trend toward better OS and PFS was observed among patients in complete remission (CR) at HCT. Within the FL group, sixteen patients had at one or more time points in their disease history had transformed FL. In contrast to the poor survival found in patients with transformed FL in previous studies, the 5‐yr OS was almost identical in patients with transformed and non‐transformed FL, 83% and 78%, respectively. In conclusion, our study supports that NMC‐HCT is a safe and efficacious treatment that can provide long‐term survival in elderly, heavily pretreated patients with FL and CLL. Especially patients with FL, and also transformed FL, seemed to have a great benefit of NMC‐HCT, and CR at the time of HCT was an important prognostic factor.

Limiting dilution analysis of interleukin-2 producing helper T-cell frequencies as a tool in allogeneic hematopoietic cell transplantation.

Background. A reliable in vitro test that estimates the level of ongoing alloreactivity would be valuable in allogeneic hematopoietic cell transplantation (HCT) as a help to guide clinical interventions such as donor lymphocyte infusions and changes in the immunosuppression. In the present study, the use of limiting dilution analysis of interleukin-2 (IL-2) producing helper T lymphocyte frequencies (HTL assay) as a way to quantify alloreactivity following HCT was investigated. Methods. Serial HTL assays were performed following allogeneic HCT with myeloablative or nonmyeloablative conditioning in 26 patients with hematologic malignancies. Results. Deviations from single-hit kinetics were frequently observed in the HTL assays and a nonlinear model was therefore used for analysis. The results of this analysis suggested the presence of an inhibitory cell population. Inhibition was observed in the majority of patients and was not restricted to a specific transplant regimen. Inhibition occurred more often with high frequencies of IL-2 producing cells, indicating a physiological role of the putative inhibitory cell population in the regulation of an immune response. Higher frequencies of IL-2 producing cells were observed in patients with acute graft-versus-host disease grades II-IV than in patients with grades 0-I (P = 0.046), indicating that the degree of ongoing alloreactivity is indeed quantified by the HTL assay. Conclusions. We find that the HTL assay may yield interesting insight into regulation of immune responses following allogeneic HCT, but because of the complexity of the results obtained, its use as a routine procedure to guide immunosuppression cannot be recommended.

Natural T-cell responses against minor histocompatibility antigen (mHag) HY following HLA-matched hematopoietic cell transplantation: what are the requirements for a 'good' mHag?

Allogeneic hematopoietic cell transplantation (HCT) represents a potentially curative treatment modality for several hematologic malignancies. Conventional myeloablative conditioning regimens are associated with high treatment-related mortality. To this end, the introduction of nonmyeloablative (NMA) conditioning implies that older and more frail patients can be offered HCT, and recent data suggest comparable outcome of conventional and NMA–HCT, both with regards to efficacy and side effects, at least for selected indications.1 The curative principle in allogeneic HCT with NMA conditioning is solely related to the graft-versus-leukemia (GVL) effect, and several lines of evidence strongly suggest that donor T cells are the main effectors. In human leukocyte antigen (HLA), identical sibling HCT, T-cell responses to minor histocompatibility antigens (mHags) are—at least in part—responsible for the GVL effect but also cause graft-versus-host disease (GVHD). GVHD represents a major side effect of HCT, and it is well established that there exists correspondence between the GVL effect and GVHD. As a consequence, increased knowledge concerning mechanisms at play and the targets recognized may set the stage for development of treatment strategies that focus on induction of GVL in the absence of GVHD.2 Obviously, increased insight into the cells, molecules and antigens involved with GVL and GVHD are important to possibly be able to control and direct these events more precisely.

Mononuclear Cell Telomere Attrition Is Associated with Overall Survival after Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancies

After allogeneic hematopoietic cell transplantation (allo-HCT), transplanted cells rapidly undergo multiple rounds of division. This may cause extensive telomere attrition, which could potentially prohibit further cell division and lead to increased mortality. We therefore characterized the development in telomere length after nonmyeloablative allo-HCT in 240 consecutive patients transplanted because of hematologic malignancies and tested the hypothesis that extensive telomere attrition post-transplant is associated with low overall survival. Telomere length was measured using quantitative PCR in mononuclear cells obtained from donors and recipients pretransplant and in follow-up samples from recipients post-transplant. Telomere attrition at 9 to 15 months post-transplant was calculated as the difference between recipient telomere length at 9 to 15 months post-transplant and donor pretransplant telomere length, divided by donor pretransplant telomere length. Although allo-HCT led to shorter mean telomere length in recipients when compared with donors, recipients had longer mean telomere length 9 to 15 months post-transplant than they had pretransplant. When compared with donor telomeres, recipients with extensive telomere attrition at 9 to 15 months post-transplant had low overall survival (10-year survival from 9 to 15 months post-transplant and onward: 68% in the tertile with least telomere attrition, 57% in the middle tertile, and 39% in the tertile with most attrition; log-rank P = .01). Similarly, after adjusting for potential confounders, recipients with extensive telomere attrition had high all-cause mortality (multivariable adjusted hazard ratio, 1.84 per standard deviation of telomere attrition at 9 to 15 months post-transplant; 95% confidence interval, 1.25 to 2.72; P = .002) and high relapse-related mortality (subhazard ratio, 2.07; 95% confidence interval, 1.14 to 3.76; P = .02). Taken together, telomere attrition may be a clinically relevant marker for identifying patients at high risk of mortality.