Thomas Kiss

Long-term follow-up of secondary malignancies in adults after allogeneic bone marrow transplantation.

Summary:The purpose of this study was to evaluate the estimated incidence of secondary malignancies post-allogeneic bone marrow transplantation (BMT) in a cohort of adult patients previously reported now with an additional 8.5 years of follow-up. A cohort of 557 patients older than age 16 years underwent allogeneic BMT between June 1970 and November 1993. Histologic reports confirmed the diagnosis of a secondary malignancy. Multivariate Cox proportional hazards method was utilized to investigate predictors for the development of secondary malignancies. In all, 31 patients in this cohort developed a secondary malignancy a median of 6.79 years after their transplant. The estimated cumulative incidence rate of secondary malignancy was 4.2% at 10 years post transplant. When compared to the general population, the estimated observed/expected ratio of new cancer diagnoses was 5.13. On multivariate analysis, older age at the time of transplant was the only significant predictor for development of secondary cancer (P=0.01). The most common malignancies observed were nonmelanomatous skin cancers and squamous cell cancers of the buccal cavity. The risk of developing a secondary malignancy after allogeneic BMT is significant, particularly in older patients. Long-term survivors of transplant require regular monitoring for early signs of cancer, particularly of the skin and oral cavity.

RBC transfusion requirements after allogeneic marrow transplantation: impact of the before-transplant Hb level on transfusion and early survival

BACKGROUND : Most patients undergoing allogeneic marrow transplantation (alloBMT) require transfusions of RBCs. A retrospective analysis was performed to evaluate the utilization and risk factors for RBC transfusions including age and sex of recipient, HLA matching between donor and recipient, disease status at time of BMT, the occurrence of GVHD, ABO blood group compatibility, the source of progenitor cells and the Hb level before BMT (PT‐Hb).

High incidence of herpes zoster in nonmyeloablative hematopoietic stem cell transplantation.

Although the use of nonmyeloablative (NMA) hematopoietic stem cell transplantation (HSCT) regimens has expanded in the past decade, little data exist to support antiviral prophylaxis to prevent herpes zoster (HZ) in recipients who are seropositive for varicella-zoster virus in this population. The present study examined the clinical features, incidence, and risk factors for HZ in a homogeneous cohort of NMA allogeneic HSCT recipients. We conducted a retrospective cohort study assessing all patients who underwent sibling NMA HSCT at Maisonneuve-Rosemont Hospital (Montreal) between July 2000 and December 2008. All patients received the same conditioning regimen, immunoprophylaxis, and graft-versus-host disease therapy. The diagnosis of HZ was defined clinically. Factors associated with HZ were identified using a Cox proportional hazards model. A total of 179 patients were followed for a median of 33 months (interquartile range, 21-59). HZ developed in 66 patients (37%) at a median of 8.3 months post-HSCT; the incidence rate was 175 cases/1000 person-years. The estimated cumulative HZ incidence was 27% at 1 year, 36% at 2 years, and 44% at 3 years. Thoracic dermatomes were most frequently involved (30%); dissemination occurred in 5 patients. No deaths resulted from HZ, but 23% of patients developed postherpetic neuralgia. In multivariate analysis, reactivation of cytomegalovirus and herpes simplex virus was associated with a reduced likelihood of HZ (hazard ratio, 0.54 and 0.33, respectively). Antiviral prophylaxis or treatment for cytomegalovirus and herpes simplex virus reactivations were protective against HZ. The incidence of HZ in our cohort of NMA HSCT recipients is similar to the incidence reported in HSCT recipients who received a myeloablative conditioning regimen. Given the observed high risk, we conclude that recommendations for antiviral prophylaxis should apply, at least for the first year, to the NMA HSCT population as well.

Blood and marrow transplantation in elderly acute myeloid leukaemia patients – older certainly is not better

Acute myeloid leukaemia in the elderly is a disease with distinct biological properties, commonly associated with leukaemic cell treatment resistance and with an increased number of high-risk features, including concomitant myelodysplasia and poor-risk cytogenetic abnormalities such as monosomy 5 and 7. Complete remission rates after standard induction chemotherapy in patients above age 60 years are less than 50%, with long-term survival rates below 10%. Post-remission stem cell transplant therapies have not been studied extensively. Autologous transplants can result in an acceptable 3-year leukaemia-free survival rate of up to 47%, yet this procedure is applicable only to a small minority of patients. Myeloablative allogeneic transplants similarly show feasibility in selected few patients and in general are very toxic. Non-myeloablative allogeneic transplants are associated with reduced toxicity, but are plagued by an increased relapse rate. The latter strategy appears promising, but must be validated in larger, multi-centre prospective trials, in which outcomes are compared to non-transplant approaches.

Bone marrow aspirates as part of routine donor assessment for allogeneic blood and marrow transplantation can reveal presence of occult hematological malignancies in otherwise asymptomatic individuals.

Summary:Pre transplant screening work-up of donors for allogeneic blood and marrow transplantation is essential in an effort to minimize risks to the recipient and protect the donor. At Princess Margaret Hospital, every potential donor is screened with a bone marrow aspirate. The case histories of three asymptomatic potential donors who presented within 1 year with normal complete blood counts, history and physical examination are presented. A 65-year-old male patient was diagnosed with smouldering multiple myeloma, a 72-year-old male patient with chronic lymphocytic leukemia and a 42-year-old male patient with myelodysplastic syndrome. Bone marrow examination led to the diagnosis in each one of these cases. Of note is that each of the potential donors was discovered to have the same disease as the transplant recipient. In vitro clonogenic hemopoietic progenitor assays were compared to those of 20 normal volunteers. Inferior growth of hemopoietic progenitor colonies in all three was noted. In conclusion, particularly in older donors and donors with potential for familial malignancies, more screening investigations including bone marrow aspiration may be reasonable to investigate for occult hematological malignancies prior to stem cell donation. Clonogenic assays can contribute to detect hemopoietic abnormalities pre transplant.

Tandem Autologous–Allogeneic Nonmyeloablative Sibling Transplantation in Relapsed Follicular Lymphoma Leads to Impressive Progression-Free Survival with Minimal Toxicity

Autologous stem cell transplantation (ASCT) prolongs survival in patients with relapsed follicular lymphoma. ASCT is usually not curative, however. Myeloablative allogeneic transplantation has produced long-term survival at a cost of significant transplantation-related mortality (TRM), whereas reduced-intensity transplantation entails less TRM but has a higher relapse rate. We thus initiated a protocol consisting of ASCT followed by nonmyeloablative allogeneic transplantation (NMT) for relapsed follicular lymphoma to mimic myeloablative allogeneic transplantation without the associated toxicity. The NMT was non-T cell-depleted, and all donors were HLA-identical siblings. We report results in 27 patients with a median age of 49 years (range, 34-65 years). Five patients demonstrated histological progression toward an aggressive lymphoma. The patients had received a median of 3 lines of previous therapy. Disease status before ASCT included 8 patients in complete remission, 14 in partial remission, and 5 refractory. Five patients developed grade II-IV acute graft-versus-host disease, and 20 patients developed chronic graft-versus-host disease requiring systemic therapy. With a median follow-up of 39 months after NMT, overall survival and progression-free survival were 96% at 3 years. We conclude that the combined ASCT-NMT strategy appears to be safe, with excellent progression-free survival even in refractory and transformed cases. This novel approach warrants further investigation in larger prospective studies.

Stem cell transplantation for mantle cell lymphoma: if, when and how?

Summary:Although the prognosis for mantle cell lymphoma (MCL) patients has improved in recent years, the outlook for those with advanced or recurrent disease remains poor. High-dose chemotherapy and autografting performed early in responding patients appears to be a method to extend progression-free survival (PFS) and overall survival (OS). The use of monoclonal antibody therapy added into the initial therapy and in the peritransplant period may improve on these results. Myeloablative allogeneic transplant appears to be a modality capable of providing curative therapy, but is plagued by a high treatment-related mortality, especially in older patients. Reduced-intensity conditioning allografting have fewer problems associated with the initial phase of transplant and hence may be preferred for those patients for whom an allograft is considered but have comorbid conditions or age issues that preclude a full allograft. Long-term results are lacking and the side effects associated with chronic GVHD may be as significant and debilitating. Trials designed to look at newly diagnosed patients with MCL examining the outcomes after planned autologous and allogeneic transplant as part of the initial management are needed to confirm the role of these various modalities in the overall therapy of this poor-outcome lymphoma.

Favorable long-term outcome of patients with multiple myeloma using a frontline tandem approach with autologous and non-myeloablative allogeneic transplantation

Despite survival improvement with novel agents and use of autologous hematopoietic stem cell transplantation (HSCT), cure of patients with multiple myeloma (MM) remains anecdotal. Initial observations suggested that chronic GvHD was accompanied by an anti-myeloma effect after myeloablative HSCT, but unfortunately this procedure was hampered by high non-relapse mortality (NRM). To maximize the anti-myeloma effect and minimize NRM, we developed a non-myeloablative (NMA) regimen associated with a high incidence of chronic GvHD and tested its efficacy on patient survival and disease eradication. From 2001 to 2010, 92 patients aged⩽65 years with a compatible sibling donor received autologous HSCT followed by an outpatient NMA allogeneic HSCT using a conditioning of fludarabine and cyclophosphamide. Patient median age was 52 years and 97% presented Durie–Salmon stages II–III disease. After a median follow-up of 8.8 years, probability of 10-year progression free and overall survival were 41% and 62%, respectively. Although the cumulative incidence of extensive chronic GvHD was high (at 79%), the majority of long-term survivors were off immunosuppressive drugs by year 5 and NRM was low (at 10%). Together, our results suggest that potential MM cure can be achieved with NMA transplantation regimens that maximize graft-versus-myeloma effect and minimize NRM.

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).