Ahsan Chaudhry

High-dose thiotepa, busulfan, cyclophosphamide and ASCT without whole-brain radiotherapy for poor prognosis primary CNS lymphoma

Summary:Treatment of primary central nervous system lymphoma (PCNSL) with combined high-dose methotrexate (HD-MTX)-based chemotherapy and whole-brain radiotherapy (WBRT) is associated with severe neurotoxicity, but high relapse rates are associated with the use of either modality alone. In an attempt to improve upon these dismal results, we treated seven PCNSL patients with HD-MTX-based induction therapy followed by thiotepa, busulfan, cyclophosphamide (TBC), and autologous stem cell transplant (ASCT), without WBRT. Six of these patients had at least one of the following poor prognostic features: Karnofsky performance status (KPS) ⩽50%, age >60 years, or relapsed disease. All but one patient tolerated the treatment well and experienced improvements in neurological function and overall performance status post-transplant. No treatment-induced neurotoxicity (dementia, ataxia, and incontinence) was observed although the follow-up is short. One early treatment-related death occurred in a patient with multiple comorbid medical conditions. The other six patients achieved a complete response (CR) after TBC and ASCT. Five patients are currently alive and relapse-free at 5, 8, 24, 36, and 42 months from diagnosis. One additional patient relapsed and died 33 months after diagnosis. Two of the seven patients received TBC/ASCT as the only treatment after disease progression following their initial chemotherapy and both remain relapse-free at the time of this report, 22 and 31 months post-TBC/ASCT. In conclusion, prolonged CR can be attained after chemotherapy-only treatment of poor prognosis PCNSL. Furthermore, this small series suggests that high-dose chemotherapy for PCNSL should include drugs that penetrate the CNS such as busulfan and thiotepa rather than standard lymphoma regimens such as BEAM.

Unrelated donor BMT recipients given pretransplant low-dose antithymocyte globulin have outcomes equivalent to matched sibling BMT: A matched pair analysis

Fifty-seven patients receiving unrelated donor (UD) BMT were matched for disease and stage with 57 recipients of genotypically matched related donor (MRD) BMT. All UD recipients were matched serologically for A and B and by high resolution for DR and DQ antigens. All patients received CsA and ‘short course’ methotrexate with folinic acid. Unrelated donor BMT patients also received thymoglobulin 4.5 mg/kg (6 mg/kg if <30 kg) in divided doses over 3 days pretransplant. For UD and RD BMT, respectively, incidence of acute GVHD grade II–IV was 19 ± 6% vs 36 ± 8%, grade III–IV 10 ± 6% vs 18 ± 7%, chronic GVHD 44 ± 8% vs 51 ± 8%, non-relapse mortality 15 ± 5% vs 8 ± 4% at 100 days, 28 ± 8% vs 36 ± 7% at 3 years. At 3 years, relapse was 45 ± 7% vs 42 ± 7%, and disease-free survival 39 ± 7% vs 37 ± 7%. None of these differences are significant. Three-year overall survival was identical at 42 ± 7%. For 29 patients with low/intermediate risk leukemia, disease-free survival was 68 ± 10% after UD BMT vs 59 ± 9% for RD BMT recipients (P = NS). Corresponding figures for high risk patients were 14 ± 7% and 21 ± 8%, respectively. We conclude that UD BMT recipients matched as above and given pretransplant ATG have similar outcomes to recipients of MRD BMT using conventional drug prophylaxis. Unrelated donor BMT should be considered in any circumstance where MRD BMT is routine.

Superior autologous blood stem cell mobilization from dose-intensive cyclophosphamide, etoposide, cisplatin plus G-CSF than from less intensive chemotherapy regimens

The study purpose was to determine if G-CSF plus dose-intensive cyclophosphamide 5.25 g/m2, etoposide 1.05 g/m2 and cisplatin 105 mg/m2 (DICEP) results in superior autologous blood stem cell mobilization (BSCM) than less intensive chemotherapy. From January 1993 until May 1997, 152 consecutive patients with non-Hodgkin’s lymphoma (n = 55), breast cancer (n = 47), Hodgkin’s disease (n = 14), multiple myeloma (n = 9), AML (n = 9), or other cancers (n = 18) initially underwent BSCM by one of three methods: Group 1: G-CSF alone × 4 days (n = 30). Group 2: disease-oriented chemotherapy, dosed to avoid blood transfusions, followed by G-CSF starting day 7 or 8, and apheresis day 13 or 14 (n = 82). Group 3: DICEP days 1–3, G-CSF starting day 14, and apheresis planned day 19, 20 or 21 (n = 40). A multivariate analysis was performed to determine which factors independently predicted BSCM. The median peripheral blood CD34+ (PB CD34+) cell count the morning of apheresis linearly correlated with the number of CD34+ cells removed per litre of apheresis that day. The median PB CD34+ cell count and median CD34+ cells × 106 removed per litre of apheresis were highest for Group 3, intermediate for Group 2, and lowest for Group 1. By multivariate analysis, mobilization group (3 > 2 > 1), disease other than AML, no prior melphalan or mitomycin-C, and less than two prior chemotherapy regimens predicted better BSCM. Out of 15 Group 3 patients who had infiltrated marrows, 11 had no detectable cancer in marrow and apheresis products after DICEP. These data suggest that DICEP results in superior BSCM than less intensive chemotherapy regimens.

Early outcomes after allogeneic stem cell transplantation for leukemia and myelodysplasia without protective isolation: A 10-year experience

Although it is common practice to use some form of isolation to protect allogeneic stem cell transplant patients from infection, the necessity for these practices in all environments has not been demonstrated. The current study evaluated patterns of infection and 100-day transplant-related mortality in 288 patients with myelodysplasia and leukemia transplanted without isolation. Patients were allowed out of hospital at any time within constraints of the medication schedule. Fever, foci of infection, and positive cultures within 28 days and death within 100 days because of the transplant procedure were recorded. Fever occurred in 57% of patients, and 10% had a clinical or radiographic focus of infection. Most infections were apparently endogenous; blood cultures from 24% of recipients grew organisms, 87% of which were gram-positive bacteria. Four patients (1%) died with aspergillus infection in circumstances indicating that isolation would not have been helpful. Twenty percent of patients remained without evidence of infection throughout. Transplant-related mortality at 100 days was 1% for 108 patients with early leukemia receiving transplants from matched siblings. For patients at higher risk, by virtue of donor and/or disease status, mortality was 21%. These figures compare favorably with those reported to the International Bone Marrow Transplant Registry, the majority of patients having been subjected to some form of isolation. We conclude that allogeneic stem cell transplantation can be safely performed in some environments without confining patients continuously to the hospital.

Factors predicting engraftment of autologous blood stem cells : CD34+ subsets inferior to the total CD34+ cell dose

Data were analyzed on 178 consecutive patients (median age 43 years) who underwent autologous blood stem cell transplantation (ABSCT) at a single institution to determine if CD34+subsets (CD34+38−, CD34+33−, CD34+33+, CD34+41+) or various clinical factors affect hematopoietic engraftment independent of the total CD34+ cell dose/kg. Using Cox proportional hazards models, the factors independently associated with rapid neutrophil engraftment were higher CD34+ dose/kg, use of G-CSF post-ABSCT, and conditioning regimen (single-agent melphalan ± TBI slower). Factors independently associated with rapid platelet engraftment were higher CD34+ cell dose/kg, higher ratio of CD34+33−/total CD34+ cells infused, conditioning regimen (mitoxantrone, vinblastine, cyclophosphamide faster), and no CD34+ cell selection of the autograft. The CD34+ cell selection process seemed to deplete CD34+41+ cells to a greater extent than total CD34+cells which may explain our observation that it resulted in slower platelet engraftment. In conclusion, the total CD34+ dose/kg was a better predictor of hematopoietic engraftment following ABSCT than the dose of any CD34+ subset. Platelet engraftment, however, was also influenced by the ratio of CD34+33−/total CD34+cells for unmanipulated autografts, and possibly by the CD34+41+dose for autografts manipulated by CD34+ selection. The use of CD34+ subsets requires further investigation in predicting engraftment of autografts which undergo ex vivo manipulation.

Possible benefits of high-dose chemotherapy and autologous stem cell transplantation for adults with recurrent medulloblastoma

In an attempt to improve the dismal prognosis of adults with recurrent medulloblastoma, six patients were treated with aggressive salvage therapy including high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT). At relapse, all patients underwent surgical debulking followed by HDCT/ASCT and then radiotherapy when possible. The treatment plan included two cycles of HDCT/ASCT; first with cyclophosphamide, etoposide and carboplatin (CECb) and then 2 months later with cyclophosphamide and thiotepa (CT). Three of the six patients received the planned therapy. One patient experienced severe toxicity requiring life-sustaining therapy. This patient developed multi-organ dysfunction including multiple enhancing lesions in both cerebral hemispheres that slowly resolved over several months. Two other patients did not mobilize sufficient stem cells for two ASCT procedures. They received one ASCT conditioned with cyclophosphamide, thiotepa and carboplatin (CTCb). Three of six patients had a complete response (CR); the other three had a partial response (PR). Following the first ASCT, median duration of response was 13.5 months (range 9–29 months) and median survival was 21.5 months (range 12–42 months). There was no treatment-related mortality. We conclude that HDCT/ASCT with CECb-CT or CTCb is active against recurrent medulloblastoma in adults and may be associated with prolonged remissions. Multiple enhancing cerebral lesions on brain MRI early post-HDCT/ASCT may be a consequence of the treatment rather than metastatic disease.

Predictive factors for long-term engraftment of autologous blood stem cells

Data from 170 consecutive patients aged 19–66 years (median age 46 years) who underwent unmanipulated autologous blood stem cell transplant (ASCT) were analyzed to determine if total CD34+ cells/kg infused, CD34+ subsets (CD34+41+, CD34+90+, CD34+33−, CD34+38−, CD34+38−DR−), peripheral blood CD34+ cell (PBCD34+) count on first apheresis day, or various clinical factors were associated with low blood counts 6 months post ASCT. Thirty-four patients were excluded from analysis either because of death (n = 17) or re-induction chemotherapy prior to 6 months post ASCT (n = 13), or because of lack of follow-up data (n = 4). Of the remaining 136 patients, 46% had low WBC (<4 × 109/l), 41% low platelets (<150 × 109/l), and 34% low hemoglobin (<120 g/l) at a median of 6 months following ASCT. By Spearmans rank correlation, both the total CD34+ cell dose/kg and the PBCD34+ count correlated with 6 month blood counts better than any subset of CD34+ cells or any clinical factor. The PBCD34+ count was overall a stronger predictor of 6 month blood counts than was the total CD34+ cells/kg infused. Both factors retained their significance in multivariate analysis, controlling for clinical factors. In conclusion, subsets of CD34+ cells and clinical factors are inferior to the total CD34+ cell dose/kg and PBCD34+ count in predicting 6 month blood counts following ASCT. Bone Marrow Transplantation (2000) 26, 1299–1304.

Double high-dose therapy for Hodgkin's disease with dose-intensive cyclophosphamide, etoposide, and cisplatin (DICEP) prior to high-dose melphalan and autologous stem cell transplantation.

We previously reported a 50% (95% CI = 33–76%) 5 year event-free survival (EFS) rate for 23 patients with Hodgkins disease (HD) who received salvage therapy with single agent high-dose melphalan (HDM) and autologous stem cell transplantation (ASCT). Predictors of poor outcome included bulky disease and initial remission <1 year. since 1995, similar poor prognosis patients have been treated with double high-dose therapy consisting of dose-intensive cyclophosphamide 5.25 g/m2, etoposide 1.05 g/m2, cisplatin 105 mg/m2(DICEP) for tumor cytoreduction and stem cell mobilization followed by HDM/ASCT. The purpose of the present study is to determine if the use of DICEP is associated with improved event-free (EFS) and overall survival (OAS) for patients treated with HDM/ASCT. From February 1981 to June 1999, 46 consecutive patients received HDM/ASCT for relapsed (n = 35) or refractory (n = 11) hd. dicep re-induction and blood stem cell mobilization was used for 21 patients. factors considered for univariate and multivariate analyses included age at transplant, number of failed chemotherapy regimens, prior radiotherapy, length of initial remission, relapsed or refractory disease status, extranodal relapse, b symptoms at relapse, bulk, post-asct radiotherapy, and dicep re-induction therapy. cox proportional hazards models were constructed for both event and death. dicep and hdm were well tolerated with no early treatment-related mortality or toxicity requiring life-sustaining measures. for all 46 patients, the projected 5 year efs was 52% (95% ci = 38–72%) and oas was 57% (95% ci = 40–82). factors independently associated with relapse in multivariate analysis included bulk >5 cm (RR = 6.38, P = 0.002), prior radiotherapy (RR = 3.59, P = 0.027), and not using DICEP (RR = 5.29, P = 0.005). factors independently associated with death included bulk >5 cm (RR = 5.13, P = 0.009), ⩾3 prior chemotherapy regimens (RR = 4.72, P = 0.019), and not using DICEP (RR = 7.49, P = 0.015). This study demonstrates that DICEP re-induction prior to HDM/ASCT is feasible. The preliminary data are sufficiently encouraging to warrant a multicenter phase II or a phase III trial evaluating DICEP followed by HDM/ASCT as salvage therapy for HD. Bone Marrow Transplantation (2000) 26, 383–388.

Autologous transplantation for primary systemic AL amyloidosis is feasible outside a major amyloidosis referral centre: the Calgary BMT Program experience.

Summary:Recent reports from large amyloidosis referral centers suggest that primary systemic AL amyloidosis patients treated with high-dose melphalan (HDM) and autologous stem cell transplantation (ASCT) survive longer than historical controls treated with less intensive chemotherapy, despite high transplant-related mortality (TRM) rates of >10%. A retrospective review was conducted to determine if the outcome of ASCT for AL amyloidosis at our institution was similar to that reported at major amyloidosis referral centers. Over a 7 year period, we treated a total of 15 AL amyloidosis patients with ASCT, including four with poor prognosis cardiac or multisystem involvement. No TRM was observed. Overall, 10 patients (67%) achieved a complete hematological response and four patients (27%) achieved a complete organ response. The 4-year event-free and overall survival rates were 60% (95% CI 32–89%) and 75% (95% CI 50–100%), respectively. One patient, who presented with cardiac failure and multiorgan involvement with colonic bleeding currently remains in complete remission 62 months post-ASCT. In conclusion, ASCT for primary AL amyloidosis can safely be performed at experienced transplant centers that are not associated with major amyloidosis referral centers, and is feasible for patients who have multisystem involvement, particularly for motivated patients with good performance status.

The CD34+90+ cell dose does not predict early engraftment of autologous blood stem cells as well as the total CD34+ cell dose.

CD90 or Thy-1 is an antigen co-expressed with CD34+ on putative immature hematopoietic stem cells. Peak mobilization of CD34+90+ cells into the blood occurs a few days earlier than peak mobilization of total CD34+ cells. Because it is not known which cell type best correlates with engraftment, the optimal timing of apheresis remains unclear. The purpose of the study was to determine if the CD34+90+ cell dose predicts engraftment of autologous blood stem cells independent of the total CD34+ cell dose/kg, the dose of other CD34+ cell subsets (CD34+33−, CD34+38−, CD34+41+), or various clinical factors. Data were analyzed on 125 consecutive patients ranging in age from 19 to 66 years (median 46) who underwent autologous blood stem cell transplantation (ABSCT) for breast cancer (54), lymphoma (59), or other malignancies (12). By univariate analysis, neutrophil (⩾0.5 × 109/l) and platelet (⩾20 × 109/l or ⩾100 × 109/l) engraftment correlated better with the total CD34+ cell dose than with the CD34+90+ cell subset. Using Cox proportional hazards models, factors independently associated with both neutrophil engraftment (⩾0.5 × 109/l) and platelet engraftment (⩾20 × 109/l and ⩾100 × 109/l) were higher total CD34+ dose/kg and high-dose regimen (melphalan-containing slower than other regimens). In conclusion, the total CD34+ dose/kg was a better predictor of hematopoietic engraftment following ABSCT than the dose of any CD34+ subset, including CD34+90+ cells. Apheresis should continue to be timed according to peak CD34+ levels. Bone Marrow Transplantation (2000) 25, 435–440.