Guy Sauvageau

Allogeneic transplantation for multiple myeloma: further evidence for a GVHD-associated graft-versus-myeloma effect

We report a series of 37 consecutive patients with multiple myeloma (MM) who received an allograft between 1990 and 2000 at our institution. Median age was 47 years, and nearly 70% of patients were Durie–Salmon stage III. A median of five cycles of chemotherapy were given before transplant, with a median interval between diagnosis and transplant of 9.3 months. We report a nonrelapse mortality rate of 22% with a median follow-up period of 40 months, whereas complete remission (CR) rate at 12 months is estimated at 57%. Treatment failure rate and overall survival at 40 months are estimated at 52% and 32%, respectively. The number of chemotherapy cycles prior to allotransplantation achieved borderline statistical significance as a poor prognosis factor for overall survival (P = 0.05), while the presence of chronic graft-versus-host disease (cGVHD) was significantly correlated with CR achievement (P = 0.036). Our study confirms that early allografting in MM can yield toxicity rates significantly lower than those associated with historical cohorts, and supports the hypothesis that cumulative chemotoxicity has a negative influence on mortality and survival rates. More importantly, our study clearly demonstrates an association between cGVHD and CR and brings further evidence in favor of a graft-versus-myeloma effect. Bone Marrow Transplantation (2001) 28, 841–848.

Graft-versus-Host Disease Prophylaxis with Tacrolimus and Mycophenolate Mofetil in HLA-Matched Nonmyeloablative Transplant Recipients Is Associated with Very Low Incidence of GVHD and Nonrelapse Mortality

Incidence of grade II-IV acute graft-versus-host disease (aGVHD) in nonmyeloablative (NMA) transplant recipients remains high. To date, the ideal prophylaxis regimen, which minimizes aGVHD and chronic GVHD (cGVHD), but does not abrogate graft-versus-tumor (GVT) response, has not been described. Because tacrolimus is more potent than cyclosporine (CSA), and because mycophenolate mofetil (MMF) is an effective immunosuppressant that does not lead to mucositis, we hypothesized that a combination of these 2 oral agents may be an effective GVHD prophylactic strategy. We, therefore, designed an outpatient prospective cohort study with a conditioning regimen consisting of fludarabine (Flu) 30 mg/m2 daily and cyclophosphamide (Cy) 300 mg/m2 daily for 5 days followed by infusion of blood stem cells. Tacrolimus 3mg twice a day was started on day (D) -8, adjusted to achieve levels 10-15 nmol/L, continued until D +50 and then tapered by D +100 or +180 according to estimated risk of relapse. MMF 1000 mg twice a day was started on D +1 and discontinued on D +50. To date, 131 patients (males/females: 75/56) with a median age of 54 years have received a 6/6 matched sibling transplant using this protocol. Indication for NMA transplant included age >55 years (24%), expected increased risk of toxicity (28%), or participation in a multiple myeloma (MM) sequential protocol (48%). Most common diagnoses included MM (N = 62), non-Hodgkin lymphoma (NHL, N = 46), and acute leukemia (N = 10). Following infusion of 6.8 x 10(6) CD34+ cells/kg (range: 0.30-22.3), neutrophil and lymphocyte engraftment occurred in 95% of patients by D +180. The estimated cumulative incidence of classical grade I-IV aGVHD by D +120 was 11.6% (95% confidence interval [CI]: 7.1-18.5). No grade IV aGVHD was observed. In addition, 15 patients (12%: CI: 7.4-19.2; median D +140) developed an overlap syndrome consisting of clinical and histologic features of both aGVHD and cGVHD simultaneously. The estimated cumulative incidence of extensive cGVHD was 76.1% (95% CI: 67.4-83.9) at 2 years, with clinical features at presentation similar to other reported series. In patients developing extensive cGVHD, the probability of remaining on immunosuppression at 5 years was 34.8% (95% CI: 16.4-57.3). With a median follow-up of 982 days, the estimated probabilities of nonrelapse mortality (NRM) and overall survival (OS) were 15.5% (95% CI: 9.0-26.1) and 62.7% (95% CI: 51.4-72.1). The cumulative incidence of relapse was 30% at 7 years. Following NMA transplant, disease-free survival (DFS) was highest in recipients with follicular NHL (79.8%: 95% CI: 57.6-91.2) and lowest in large cell NHLs (34.3%: 95% CI: 1.6-75.9). From this large group of patients treated with a uniform conditioning and GVHD prophylaxis regimen, we conclude that aGVHD prophylaxis with early use of tacrolimus and MMF is safe, effective, and associated with low NRM. Future strategies will need to focus on decreasing the incidence of extensive cGVHD without increasing the risk of relapse.

Incidence and prognostic value of eosinophilia in chronic graft-versus-host disease after nonmyeloablative hematopoietic cell transplantation.

Data from a number of cohorts indicate that eosinophilia (Eo) could be associated with better outcomes following allogeneic hematopoietic cell transplant (HCT). However, little is known about its significance and prognostic value in chronic graft-versus-host disease (cGVHD) after nonmyeloablative (NMA) transplantation. Data were collected from 170 patients who underwent HCT using the same preparative regimen and GVHD prophylaxis. Donors were 6/6 HLA-matched siblings and stem cell source was peripheral blood. An eosinophil count of ≥0.5 × 10(9)/L was defined as Eo. Patients were transplanted mainly for lymphoproliferative disorders. Median age and follow-up were 54 years and 58 months, respectively. Incidents of grade II-IV acute GVHD (aGVHD) and cGVHD were 8.2% and 81.2%. Median time from HCT to cGVHD diagnosis was 142 days. Organs involved were: mouth in 80% of patients, skin in 75%, liver in 57%, eyes in 37%, gut in 14%, lungs in 5%, others in 5%. Eo was found in 44% of patients at diagnosis of cGVHD (range: 0.5-4.4 × 10(9)/L). Median time between first appearance of Eo and diagnosis of cGVHD was 4.5 days. We found no correlation between organ involvement and Eo but a lower prevalence of Eo in cGVHD associated with thrombocytopenia (P = .023). Nevertheless, we observed no association among Eo and overall survival (OS), relapse incidence, or nonrelapse mortality (NRM) in the overall cohort, nor in subsets of patients with multiple myeloma and follicular non-Hodgkin lymphoma. Although Eo is observed frequently in cGVHD following NMA transplantation, we report no correlation beween Eo and outcome.

Diphyllobothriasis, a rare cause of profuse diarrhea following autologous transplantation

Diphyllobothriasis is a zoonosis acquired by humans after the ingestion of plerocercoid larvae present in raw and undercooked fish. In North America, Diphyllobothrium latum (D. latum) infection is limited mostly to areas with cold water lakes. Various species of freshwater or anadromous (living in both fresh and saltwater) fishes may be infected by D. latum plerocercoid larvae, including perch, trout, salmon, char and pike. We report herein the first case of D. latum infection in an immunocompromised patient who presented with profuse diarrhea. The patient was a 60-year-old man who lived in the north-east area of the Province of Quebec, Canada, and who had never traveled outside the country. This patient with anaplastic T-cell lymphoma had achieved minimal residual disease with ESHAP (etoposide, methylprednisolone, cytosine arabinoside and cis-platinum) chemotherapy. He was admitted to our institution in December 2005 to undergo auto-SCT. His disease initially presented with widespread abdominal lymph nodes and multiple hepatic nodular lesions, which progressed after eight cycles of CHOP (CY, doxorubicin, VCR and prednisone). His medical history was significant for mild, chronic diarrhea (2–3 loose stools/day) of 1-year duration; complete investigation by a gastroenterologist, including upper and lower endoscopies, was negative. After conditioning with BEAC (bis-chloronitrosourea, etoposide, cytosine arabinoside and CY), the patient received his autologous stem cell graft on 29 December 2005. On day þ 3, though neutropenic, he developed fever, diffuse abdominal pain and profuse diarrhea, which reached a maximum of 5025ml/day (Figure 1). A computed tomography scan of the abdomen revealed right colitis as well as a thickening of the cecum and distal parts of the small bowel. Coprological cultures were negative for pathogenic bacteria or viruses; quantitative PCR in blood leukocytes for CMV was also negative. The patient recovered from aplasia on day þ 18 with decreased diarrhea. However, the improvement was of short duration, with recurrence of both diarrhea and fever on day þ 28 despite the resolution of aplasia (Figure 1). Multiple repeat stool cultures were unable to identify any specific pathogen. A careful physical examination showed a new right cervical lymph node. Repeat computed tomography scans of the chest and abdomen were suggestive of lymphoma relapse with recurrence of several lymph nodes in previously involved areas. Biopsy of the right cervical lymph node confirmed relapse of anaplastic T-cell lymphoma. A microbiology consultation was obtained on day þ 42; three stool specimens were sent for parasitic examination. A diagnosis of D. latum infection was made after identification of numerous characteristic parasite eggs (Figure 2). The patient received a single dose of praziquantel (10mg/kg) on day þ 43 with initial improvement in stool output. Two stool specimens became negative for parasite eggs after the first treatment. However, on day þ 49, profuse diarrhea recurred and eggs in two separate stool specimens were again identified. A second dose of

Cardiac tamponade potentially related to sirolimus following cord blood transplantation

We present the case of a 28-year-old female patient with advanced myelodysplastic syndrome. Her BM examination at diagnosis showed the presence of 16% blasts and multi-lineage dysplasia, findings consistent with refractory anemia with excess blasts-2 (RAEB-2). Cytogenetic analysis revealed a deletion 5q and the rare translocation t(3;12)(q26;p13) with rearrangement of the ecotropic viral integration-1 gene (EVI1) by FISH. An allogeneic hematopoietic SCT (HSCT) was considered to be urgent due to the high-risk nature of her disease. Unfortunately, neither a family nor a matched unrelated donor was available. We therefore decided to proceed with a cord blood transplantation from a 6/6 HLA-matched donor. The unit contained a total nucleated cell dose of 3.87 × 107/kg; both donor and recipient were seronegative for CMV. The preparative regimen included fractioned TBI (12 Gy), CY (120 mg/kg) given over two days and fludarabine (75 mg/m2) in three doses. GVHD prophylaxis consisted of tacrolimus (beginning on day −3) and mycophenolate mofetil (as of day +1).

Late acute renal failure due to bilateral kidney infiltration by ALL as single manifestation of relapse after allogeneic transplantation

Late acute renal failure due to bilateral kidney infiltration by ALL as single manifestation of relapse after allogeneic transplantation