Radovan Saso

A low CD34+ cell dose results in higher mortality and poorer survival after blood or marrow stem cell transplantation from HLA-identical siblings : should 2 x 106 CD34+ cells/kg be considered the minimum threshold?

We studied the effect of the CD34+ cell dose on transplant-related mortality (TRM) and survival in 39 patients randomized to receive lenograstim-mobilized PBSCT (n= 20) or BMT (n = 19) from HLA-identical siblings. Both marrow and blood were harvested, and one infused in a double-blind fashion. The median nucleated (7.0 vs 3.2 × 108/kg; P < 0.0001), cd34+ (3.7 vs 1.5 × 106/kg; P = 0.002), CFU-GM (42 vs 19 × 104/kg; P= 0.002), and CD3+ (1.9 vs 0.3 × 108/kg; P < 0.0001) cell doses with pbsct were higher. thirteen patients (6 bmt and 7 pbsct) experienced trm at 15–733 days (median 57); 10 of 20 receiving <2 × 106 CD34+ cells/kg compared with three of 19 receiving ⩾2. Eight of 20 patients receiving <2 × 106 CD34+ cells/kg are alive compared with 14 of 19 receiving ⩾2. In Cox analysis, CD34+ cell dose ⩾2 × 106/kg was associated with lower TRM (RR 0.2, P = 0.01), and higher overall (RR 3.7, P = 0.01) and event-free (RR 3.2, P = 0.02) survival. Other cell populations and the source of stem cells did not affect TRM or survival. We conclude that 2 × 106 CD34+ cells/kg may be the ideal minimum cell dose for allogeneic transplantation although lower doses do not preclude successful therapy. Since the likelihood of obtaining this threshold CD34+ cell number is significantly greater from blood than marrow, PBSCT may be preferable to marrow for allografts from HLA-identical siblings. Bone Marrow Transplantation (2000) 26, 489–496.

The impact of extramedullary disease at presentation on the outcome of myeloma

This study was conducted to compare the presenting features and outcome of newly-diagnosed myeloma with and without extramedullary (EM) manifestations and to determine the optimum treatment. Seventy-five (16.3%) patients with EM involvement at diagnosis were compared with 384 cases without EM disease. EM patients had a more favourable International Staging System and a different distribution of myeloma isotypes. When adjusted according to the independent risk factors, patients in the EM group treated with chemotherapy alone had significantly shorter overall survival (OS) compared to those without EM disease receiving similar treatment. High-dose treatment (HDT) was associated with significantly improved OS in both groups; however, it had more impact on OS among EM group, overcoming the negative prognostic impact of presenting EM disease. Patients in the EM group treated with HDT have a similar outcome to those without EM manifestations treated with HDT. HDT should form an integral component of first-line treatment for patients with EM disease whenever possible.

High-grade transformation in splenic marginal zone lymphoma with circulating villous lymphocytes: the site of transformation influences response to therapy and prognosis

In a series of 48 patients with splenic marginal zone lymphoma (SMZL) with circulating villous lymphocytes, we describe the clinical and laboratory features of nine cases that transformed to high‐grade B‐cell lymphoma. These patients had a significantly greater incidence of peripheral lymph node involvement at diagnosis when compared to SMZL patients who did not transform (P < 0·03). While transformation in the bone marrow is frequently refractory to therapy and associated with poor outcome in SMZL, lymph node transformation responds well to chemotherapy with durable progression‐free and overall survival.

The combination of cyclophosphomide, thalidomide and dexamethasone is an effective alternative to cyclophosphamide-vincristine-doxorubicin-methylprednisolone as induction chemotherapy prior to autologous transplantation for multiple myeloma: a case-matched analysis

A retrospective case-matched study was conducted to compare the oral regimen CTD (cyclophosphamide – thalidomide – dexamethasone) and infusional CVAMP (cyclophosphamide – vincristine – doxorubicin – methylprednisolone) as induction therapy followed by autologous peripheral blood stem-cell transplantation (PBSCT) for newly diagnosed multiple myeloma patients. The response rate after three cycles of treatment was statistically higher with CTD (n = 27) compared to CVAMP (n = 27) (89% vs. 56%, P = 0.016). Toxicity studies showed more neutropenia (grade 3/4) (4% vs. 60%, P = 0.0002) with CVAMP and more thrombotic episodes with CTD (11% vs. 4%). CTD may emerge as the superior induction regimen prior to PBSCT, in terms of high efficacy and better tolerability.

Long-term outcomes of previously untreated myeloma patients: responses to induction chemotherapy and high-dose melphalan incorporated within a risk stratification model can help to direct the use of novel treatments

Induction chemotherapy followed by high‐dose melphalan (HDM) is the standard treatment for fitter patients with myeloma. The place of bortezomib and the thalidomide analogues within this treatment paradigm is yet to be established. We sought to identify patients who may benefit from the introduction of novel agents during their initial management. An intention‐to‐treat analysis was performed on 383 patients with newly diagnosed myeloma eligible for HDM to determine whether the extent of response to induction therapy and HDM correlated with long‐term survival. Early response [complete response (CR) and partial response (PR)] to induction therapy was predictive of overall survival (OS) [median OS, 7·47 years for responders (CR and PR) versus 4·89 years for non‐responders; P = 0·035]. The attainment of CR at 3 months post‐HDM correlated with a prolonged progression‐free survival (PFS) (median PFS, 7·4 years in CR group versus 5·3 years in non‐CR group; P = 0·023). This data suggests that, at every stage of treatment, the aim should be to achieve CR. Patients with suboptimal responses could be offered alternative therapy. We propose a multiparametric risk‐adapted model that includes response to induction chemotherapy and HDM, for identifying patients who may benefit from novel approaches to treatment.

Thalidomide after allogeneic haematopoietic stem cell transplantation: activity in chronic but not in acute graft-versus-host disease

Summary:Thalidomide was used to treat acute (n=21) or chronic (n=59) graft-vs-host disease (GVHD) in 80 haematopoietic stem cell allograft recipients after failure to respond to the combination of cyclosporine and corticosteroids with or without other agents. The median time to onset of acute GVHD was 11 days, and thalidomide was started at a median of 48 days post transplant. In addition to corticosteroids and cyclosporine, 13 patients had also received other agents before thalidomide. None of the patients responded and all died of acute GVHD. For chronic GVHD (limited in 13, extensive in 46), thalidomide was started at a median of 385 days post transplant. In addition to corticosteroids and cyclosporine, 34 patients received azathioprine concomitantly. In all patients, thalidomide was added to the ongoing immunosuppressive regimen. The median duration of therapy with thalidomide was 60 days (range, 11–1210; <2 weeks in 11). In total, 13 patients (22%) had complete response, eight (14%) partial response and 38 (64%) no response. Response rates were comparable for limited (39%) and extensive (33%) chronic GVHD. At a median of 53 months, 19 patients are alive, 13 without evidence of chronic GVHD. Survival was significantly better in patients who responded to thalidomide. The principal causes of death were progressive chronic GVHD (n=29) and relapsed leukaemia (n=7). In conclusion, thalidomide has no activity in acute GVHD, but has some activity in chronic GVHD in combination with other agents.

Comparison of marrow and blood cell yields from the same donors in a double-blind, randomized study of allogeneic marrow vs blood stem cell transplantation.

Forty healthy adult donors underwent marrow (BM) as well as peripheral blood (PBSC) stem cell collections for their HLA-identical adult siblings with hematologic malignancies. BM was harvested on day 1 (target 3 × 108 nucleated cells/kg, 10 μg/kg lenograstim (glycosylated G-CSF) administered on days 2–6, and a single leukapheresis performed on day 6. The blood volume processed was the higher of 200% donor blood volume or 10 liters. The total nucleated cell (TNC) yields from PBSC were 1.1- to 4.3-fold higher than BM (median 7.0 vs 3.1 × 108/kg, P 7lt; 0.0001). Although bm contained a higher proportion of cd34+cells (1.3% vs 0.7%, P < 0.0001) and a comparable proportion of cd3+ cells (median 29% vs 26%, P = 0.4), the absolute numbers of CD34+ and CD3+ cells and their subsets were several times higher in PBSC. There was a poor correlation between BM and PBSC CD34 and TNC numbers, but a significant correlation between BM and PBSC CD3 numbers. Only five of 40 BM harvests contained ⩾2 × 106 CD34+ cells/kg compared with 35 of 40 PBSC harvests (P < 0.0001). we conclude that the numbers of progenitor and immunocompetent cells in pbsc are several times higher than in bm. it is possible to collect adequate numbers of progenitor cells from blood after lenograstim stimulation more frequently than from marrow, and donors yielding low quantities of progenitor cells from bm usually deliver better quantities from pbsc. Bone Marrow Transplantation (2000) 25, 501–505.

Secondary myelodysplastic syndrome/acute myeloid leukaemia following mitoxantrone-based therapy for breast carcinoma

Of 1774 patients with breast cancer given mitoxantrone (MTZ) with methotrexate (n = 492) or with methotrexate and mitomycin C (n = 1282), nine developed MDS/AML after a median of 2.5 years. Median duration of survival from diagnosis of MDS/AML was 10 months and six patients died. The crude incidence of developing MDS/AML after MMM or MM chemotherapy was 15 per 100 000 patient years follow-up, while the actuarial risk was 1.1% and 1.6% at 5 and 10 years respectively. MTZ-based regimens carry a 10 × higher risk of subsequent MDS/AML compared to that seen in the general population.

Recombinant tissue plasminogen activator (rtPA) for the treatment of hepatic veno-occlusive disease (VOD)

Seventeen patients who developed hepatic veno-occlusive disease (VOD) following hematopoietic stem cell transplantation were treated with recombinant tissue plasminogen activator (rtPA) with or without heparin. rtPA was started a median of 13 days post transplant (range 4–35). All patients received rtPA at a dose of 10 mg/day as a starting dose, and 12 patients also received heparin (1500 U bolus; then 100 U/kg/day as a continuous i.v. infusion). The median number of days of rtPA therapy was 2.5 (1–12). The median total serum bilirubin level was 116 mmol/l (range 63–194) at the beginning of treatment. Six patients showed a response to rtPA treatment (29%). It was observed that by day 2 of rtPA therapy, bilirubin levels in responders showed a downwards trend as compared to those in non-responders. In all except one patient this response was observed after two doses of rtPA. Seven out of the 11 non-responders had a past history of liver dysfunction, compared with none of the responders. There were no differences between the two groups in terms of day of onset of liver dysfunction, manifestations of disease, maximum bilirubin and creatinine levels, and day of commencing treatment. No patient experienced severe hemorrhagic complications during therapy. Four responders survived for more than 100 days compared to none of the non-responders. Probability of survival was 33% at day 100. It is difficult to unequivocally establish the role of rtPA in the treatment of VOD. The importance of bilirubin levels on days 2 or 3 of therapy in predicting outcome should be established, as should the optimum dose of rtPA and optimum duration of therapy.

Long-Term Follow-Up of Relapsed Acute Leukemia Treated with Immunotherapy After Allogeneic Transplantation: the Inseparability of Graft-Versus-Host Disease and Graft-Versus-Leukemia, and the Problem of Extramedullary Relapse

Long-term outcome of 23 acute myeloid (AML, n=16) or lymphoblastic (ALL, n=7) leukemia patients who had received immunotherapy for treatment of persistent or recurrent disease 1.5-26 (median 4) months after allogeneic transplantation was studied to determine eventual survival. Immune manipulation comprised donor leukocyte infusion (n=18), interferon-alpha2b and/or interleukin-2 (n=15), and cyclosporine withdrawal (n=11) in various combinations. Graft-versus-host disease (GVHD) developed in 12 patients. Thirteen of 20 evaluable patients responded; 6 relapsing again. Eight patients died of toxicity, and 10 of progressive disease at 3-206 weeks (median 11). Five patients (3 AML, 2 ALL) are alive in remission with GVHD 2-46 months (median 23) after immunotherapy with Karnofsky scores of 70-100% (median 80). The overall survival of the whole group is 1-206 weeks (median 12), with an actuarial survival of 22% at 2 years. The development of GVHD was associated with superior survival in multivariate analysis (P=.007). Seven patients received immunosuppression because of the severity of GVHD (grade III/IV acute or extensive chronic): 3 died of GVHD, 3 improved but relapsed concomitantly, and 1 is alive in remission with extensive chronic GVHD. Four episodes of extramedullary relapse (granulocytic sarcomas) were seen in 3 patients with AML whose marrow remained in remission. We conclude that GVHD appears to be inseparable from graft-versus-leukemia in relapsed acute leukemia patients undergoing immunotherapy with a high proportion of patients dying due to toxicity or progressive disease, and isolated extramedullary relapse seems to be unusually common.