Manuel N. Fernández

Outcome of Cord-Blood Transplantation from Related and Unrelated Donors

Background Cord-blood banks have increased the use of cord-blood transplantation in patients with hematologic disorders. We have established a registry containing information on the outcome of cord-blood transplantation. Methods We sent questionnaires to 45 transplantation centers for information on patients receiving cord-blood transplants from 1988 to 1996. Reports on 143 transplantations, performed at 45 centers, were studied, and the responses were analyzed separately according to whether the donor was related or unrelated to the recipient. Results Among 78 recipients of cord blood from related donors, the Kaplan–Meier estimate of survival at one year was 63 percent. Younger age, lower weight, transplants from HLA-identical donors, and cytomegalovirus-negative serologic results in the recipient were favorable prognostic factors. Graft-versus-host disease of at least grade II occurred at estimated rates of 9 percent in 60 recipients of HLA-matched cord blood and 50 percent in 18 recipients of HLA-misma...

Unrelated umbilical cord blood transplants in adults: Early recoveryof neutrophils by supportive co-transplantation of a low number of highlypurified peripheral blood CD34+ cells from an HLA-haploidentical donor

UNLABELLED OBJECTIVE, METHODS, AND RESULTS: To reduce the period of posttransplant neutropenia and related early morbidity and mortality of cord blood (CB) transplants, we assessed the feasibility of co-infusion of a low number of highly purified peripheral blood CD34+ cells from a related haploidentical donor with a CB graft. Between March 1999 and May 2002, 11 patients with high-risk hematologic malignancies were transplanted using this strategy. The seven patients who received a haploidentical peripheral blood graft and a CB graft from a sibling (6) or the father (1) had prompt recovery (9-17 days, median 10) of the absolute neutrophil count (ANC) to greater than 0.5 x 10(9)/L. Analysis of DNA polymorphisms showed initial predominance of the haploidentical genotype both in granulocytes and in mononuclear cells, and subsequent progressive replacement by cells of CB genotype until final complete CB chimerism was achieved by patients who survived for sufficient periods of time. The four patients who received maternal haploidentical cells had no significant contribution of these to blood leukocytes, although complete CB chimerism was achieved by three of them and two reached engraftment of the CB on days +20 and +36. Morbidity due to early bacterial or fungal infections was remarkably low in patients with prompt ANC recovery. CONCLUSION Our data show that co-infusion of a CB unit and a low number of haploidentical CD34+ cells may result in a shortened period of posttransplant neutropenia. This is likely the result of prompt and transient engraftment of the haploidentical hematopoietic stem cells that may provide the patient antimicrobial protection until the later engraftment of the CB hematopoietic stem cells.

Cord blood transplants supported by co-infusion of mobilized hematopoietic stem cells from a third-party donor

This open label clinical study provides updated evaluation of the strategy of single unit cord blood transplants (CBTs) with co-infusion of third-party donor (TPD) mobilized hematopoietic stem cells (MHSC). Fifty-five adults with high-risk hematological malignancies, median age 34 years (16–60 years) and weight 70 kg (43–95 kg), received CBTs (median 2.39 × 107 total nucleated cell (TNC) per kg and 0.11 × 106 CD34+ per kg) and TPD-MHSC (median 2.4 × 106 CD34+ per kg and 3.2 × 103 CD3+ per kg). Median time to ANC and to CB-ANC >0.5 × 109/l as well as to full CB-chimerism was 10, 21 and 44 days, with maximum cumulative incidences (MCI) of 0.96, 0.95 and 0.91. Median time to unsupported platelets >20 × 109/l was 32 days (MCI 0.78). MCI for grades I–IV and III–IV acute GVHD (aGVHD) were 0.62 and 0.11; 12 of 41 patients (29%) who are at risk developed chronic GVHD, becoming severely extensive in three patients. Relapses occurred in seven patients (MCI=0.17). The main causes of morbi-mortality were post-engraftment infections. CMV reactivations were the most frequent, their incidence declining after the fourth month. Five-year overall survival and disease-free survival (Kaplan–Meier) were 56 % and 47% (63% and 54% for patients ⩽40 years). In conclusion, CBT with single units of relatively low cell content and 0–3 HLA mismatches is feasible as a first choice option for adult patients who lack a readily available adequate adult donor.

Cord blood transplants: early recovery of neutrophils from co-transplanted sibling haploidentical progenitor cells and lack of engraftment of cultured cord blood cells, as ascertained by analysis of DNA polymorphisms

The number of infused cells is a very important factor in cord blood transplant (CBT) engraftment. Prior ex vivo expansion of aliquots of transplanted cord blood (CB) units is being investigated as a procedure to increase engraftment potential, but results are difficult to evaluate due to a lack of markers for assessing the contribution of expanded cells. We transplanted five patients, infusing the best available CB unit and cells from a second donor simultaneously. In two patients, these cells were obtained from another frozen CB unit by CD34+positive selection and culture expansion; the other three patients received uncultured highly purified haploidentical CD34+ cells. The first two patients had DNA from the culture expanded CB cells detected only for a few days around day +11 when the absolute neutrophil count (ANC) was >200/μl; thereafter and when the ANC was <500/μl, only donor DNA from the uncultured CB was detected. For the other three patients, DNA analysis showed early and transient granulocyte engraftment of haploidentical cells, progressively replaced by the CB-derived granulocytes. We concluded that: (1) simultaneous infusion of lymphocyte-depleted HLA highly mismatched haematopoietic progenitor cells has not produced unfavourable effects for CBT; (2) the double transplant model is suitable for evaluating the engraftment potential of ex vivocultured CB cells in the clinical setting; (3) the culture conditions used did not result in early recovery of ANC; and (4) co-transplantation of purified uncultured HLA haploidentical CD34+ cells may reduce the time of neutropenia following CBT.Bone Marrow Transplantation (2001) 28, 355–363.

Diagnosis of transfusion‐associated graft‐versus‐host disease by polymerase chain reaction in fludarabine‐treated B‐chronic lymphocytic leukaemia

Summary. Transfusion‐associated graft‐versus‐host disease (TA‐GVHD), has rarely been reported associated with B‐chronic lymphocytic leukaemia (B‐CLL). We report a patient diagnosed with B‐CLL, previously treated with fludarabine, who developed TA‐GVHD after being transfused during surgery for splenectomy. Diagnosis was confirmed by polymerase chain reaction (PCR) detection of donor DNA in the patient, by amplification of Y‐chromosome sequence and analysis of minisatellite polymorphisms. B‐CLL patients treated with fludarabine appear to be at risk for TA‐GVHD and should be regarded as candidates for transfusions with irradiated blood products. This case illustrates that PCR is a rapid technique for the early diagnosis of TA‐GVHD.

Infusion of lymphocytes obtained from a donor immunised with the paraprotein idiotype as a treatment in a relapsed myeloma

A 48-year-old patient with IgA k multiple myeloma received a BMT from his HLA-matched sibling. After transplantation, the disease relapsed. Melphalan therapy followed by reinfusion of haemopoietic blood stem cells collected from the patient led to the improvement of the clinical status, although mixed chimerism and an elevated serum IgA persisted. Successful donor immunisation against an immunogenic preparation of the recipient monoclonal protein was performed before the infusion of donor T lymphocytes (DLI) into the patient. Ten weeks after the lymphocyte infusions, no monoclonal band was evidenced and donor complete chimerism was detected. The patient did not develop GVHD. Once complete remission was achieved, the idiotype vaccine was administered to the patient. Nineteen months after DLI, the patient remains in remission. Bone Marrow Transplantation (2000) 25, 1105–1108.

Management of thrombotic microangiopathy following allogeneic transplantation: what is the role of plasma exchange?

Thrombotic microangiopathy (TMA) is an infrequent but serious complication of allogeneic transplantation. The success rate of plasma exchange (PE) reported in the treatment of this entity is a controversial subject. We report the outcome of 10 patients with TMA post-allogeneic transplantation after treatment with PE. Two out of the 10 patients have not responded, five had a partial response, but died of acute GVHD or interstitial pneumonitis, and three have responded and recovered. Our study suggests that there are different degrees of TMA severity. Only mild multifactorial cases with no severe hemolysis (LDH activity <1000 u/l) may be fully resolved with pe.

Immune Haemolytic Anaemia and Renal Failure Induced by Streptomycin

A case of acute immune haemolytic anaemia and renal failure induced by streptomycin, is reported. The clinical features are similar to those in a case previously reported in which no in vitro proof of antibodies was obtained. In this case, streptomycin‐specific IgG antibodies, with both k and λ light chains, could be demonstrated. The streptomycin bound strongly to the red cell membrane, apparently through chemical groups related to the M antigen and possibly also to the D antigen. Complement‐fixation by the drug‐specific IgG antibodies, after reaction with the streptomycin‐coated red cells, could also be demonstrated. On the basis of these findings, our conclusion is that a complement‐fixing hapten‐cell mechanism was the main cause of the intravascular haemolytic episode suffered by the patient on exposure to streptomycin. This drug had been prescribed 15 years earlier for pulmonary tuberculosis and he had since injected himself with it whenever he felt ‘flu’symptoms, without harmful effects, until now.

Favourable effect of the combination of acute and chronic graft-versus-host disease on the outcome of allogeneic peripheral blood stem cell transplantation for advanced haematological malignancies.

To assess the influence of graft‐versus‐host disease (GVHD) on the outcome of patients with advanced haematological malignancies (AHM) who received a primary, unmodified allogeneic peripheral blood progenitor cells transplant (allo‐PBT) from a human leucocyte antigen (HLA) identical sibling donor, we analysed 136 patients with myeloid neoplasms (n = 70) or lymphoproliferative disorders (n = 66), transplanted at 19 Spanish institutions. Median age was 35 years (range 1–61). The cumulative incidence of relapse for all patients was 34% (95% CI, 26–42%), 41% (95% CI, 33–49) for patients without GVHD and 14% (95% CI, 3–25) (P = 0·001) for patients with acute and chronic GVHD. After a median follow‐up of 11 months (range 2–49), 60 (44%) patients remained alive with an actuarial probability of overall survival and disease‐free survival (DFS) at 30 months of 31% (95% CI, 21–41%) and 28% (95% CI, 17–39%) respectively. In patients surviving > 100 d, the low incidence of relapse in those with acute and chronic GVHD led to a DFS of 57% (95% CI, 38–76%) compared with a DFS of 34% (95% CI, 17–51%) in the remaining patients (P = 0·03). Our results indicate a reduced incidence of relapse for patients with AHM receiving an unmodified allo‐PBT and developing acute and chronic GVHD, which results in an improved DFS.

Haematopoietic transplants combining a single unrelated cord blood unit and mobilized haematopoietic stem cells from an adult HLA-mismatched third party donor. Comparable results to transplants from HLA-identical related donors in adults with acute leukaemia and myelodysplastic syndromes.

We describe results of the strategy, developed by our group, of co-infusion of mobilized haematopoietic stem cells as a support for single-unit unrelated cord blood transplant (dual CB/TPD-MHSC transplants) for treatment of haematological malignancies in adults, and a comparative analysis of results obtained using this strategy and transplants performed with mobilized haematopoietic stem cells from related HLA-identical donors (RTD) for treatment of adults with acute leukaemia and myelodysplastic syndromes. Our data show that the dual CB/TPD-MHSC transplant strategy results in periods of post-transplant neutropenia, final rates of full donor chimerism and transplant-related mortality rates comparable to those of the RTD. Final survival outcomes are comparable in adults transplanted because of acute leukaemia, with different incidences of the complications that most influence these: a higher incidence of infections related to late recovery of protective immunity dependent on T cell functions, and a lower incidence of serious acute graft-versus-host disease and relapses. Recent advances in cord blood transplant techniques allow allogeneic haematopoietic stem cell transplantation (HSCT) to be a viable option for almost every patient who may benefit from this therapeutic approach. Development of innovative strategies to improve the post-transplant recovery of T cells function is currently the main challenge to further improving the possibilities of unrelated cord blood transplantation.