Bortezomib, dexamethasone, cyclophosphamide and lenalidomide combination for newly diagnosed multiple myeloma: phase 1 results from the multicenter EVOLUTION study.

This phase 1 study (Clinicaltrials.gov: NCT00507442) was conducted to determine the maximum tolerated dose (MTD) of cyclophosphamide in combination with bortezomib, dexamethasone and lenalidomide (VDCR) and to assess the safety and efficacy of this combination in untreated multiple myeloma patients. Cohorts of three to six patients received a cyclophosphamide dosage of 100, 200, 300, 400 or 500 mg/m(2) (on days 1 and 8) plus bortezomib 1.3 mg/m(2) (on days 1, 4, 8 and 11), dexamethasone 40 mg (on days 1, 8 and 15) and lenalidomide 15 mg (on days 1-14), for eight 21-day induction cycles, followed by four 42-day maintenance cycles (bortezomib 1.3 mg/m(2), on days 1, 8, 15 and 22). The MTD was the cyclophosphamide dose below which more than one of six patients experienced a dose-limiting toxicity (DLT). Twenty-five patients were treated. Two DLTs were seen, of grade 4 febrile neutropenia (cyclophosphamide 400 mg/m(2)) and grade 4 herpes zoster despite anti-viral prophylaxis (cyclophosphamide 500 mg/m(2)). No cumulative hematological toxicity or thromboembolic episodes were reported. The overall response rate was 96%, including 20% stringent complete response (CR), 40% CR/near-complete response and 68% >or=very good partial response. VDCR is well tolerated and highly active in this population. No MTD was reached; the recommended phase 2 cyclophosphamide dose in VDCR is 500 mg/m(2), which was the highest dose tested.

High efficacy and low toxicity of APL induction with concurrent idarubicin/ATRA followed by a novel and simplified outpatient post-remission therapy using single doses of idarubicin and intermittent ATRA.

Acute promyelocytic leukemia (APL) is one of the most curable myeloid malignancies because of its great sensitivity to all-trans retinoic acid (ATRA) and response to anthracycline therapy. In an attempt to simplify post-remission therapy, deliver adequate dose of anthracycline and reduce treatment related toxicity, we entered 26 consecutively newly diagnosed, previously untreated APL patients in a pilot treatment program consisting of concurrent induction using idarubicin/ATRA followed by an exclusive outpatient post-remission therapy using single dose of idarubicin and intermittent ATRA, every 4 weeks. Of 25 evaluable patients, two (8%) died early during induction due to hemorrhagic complications, and 23 (92%) achieved complete remission. Overall survival at 4.2 years was 90% (CI 76.4-100), and 3.6 years disease-free survival was 78% (CI 60.6-95.4). The treatment outcome of this program is encouraging; however, the result of this study needs to be validated in larger cohort of patients and optimally in a randomized comparison with other current post-remission approaches.

Successful treatment of hepatic veno-occlusive disease after myeloablative allogeneic hematopoietic stem cell transplantation by early administration of a short course of methylprednisolone.

Hepatic veno-occlusive disease (VOD) is one of the most common and important regimen-related toxicities observed after hematopoietic stem cell transplantation (HSCT). There are no universally accepted preventative or therapeutic approaches for VOD. We prospectively evaluated the safety and efficacy of a short course of methylprednisolone (MP) in 48 patients undergoing allogeneic HSCT who were diagnosed with hepatic VOD. MP was administered at a dose of 0.5 mg/kg i.v. every 12 h for a total of 14 doses, and then discontinued without taper. Thirty (63%) patients responded with a reduction in total serum bilirubin of 50% or more after 10 days of treatment. In univariate analysis, non-responders had a higher total bilirubin at the start of MP therapy, more weight gain, evidence of fungal infection and platelet refractoriness. High SGPT and early engraftment were significant factors among responders. Twenty-five of the 30 responders survived up to day +100, whereas all but three non-responders died within 100 days post-HSCT, for a probability of survival of 58% among responders and 10% for non-responders. Prospective comparative studies are needed to confirm the observed encouraging outcome of MP therapy for VOD.

Azithromycin in bronchiolitis obliterans complicating bone marrow transplantation: a preliminary study.

Bronchiolitis obliterans (BO) is a serious noninfectious pulmonary complication following allogeneic bone marrow transplantation (BMT). Azithromycin, a macrolide antibiotic, may have a beneficial effect in BO through its anti-inflammatory effect. The aim of the current study was to investigate the potential effect of azithromycin on pulmonary function tests (PFTs) in BO complicating BMT. PFTs of 153 post-BMT patients were followed; eight patients out of 153 (12%) developed obstructive airway disease on their PFTs, along with characteristic findings of BO on high-resolution computed tomography of the chest. These patients were given azithromycin 500 mg q.d. for 3 days, followed by 250 mg three times a week for 12 weeks. Clinically significant improvements were achieved both in forced vital capacity, where the mean (95% confidence interval) increase reported was 410 mL (0.16-0.65), which was an average improvement of 21.57%, and in the forced expiratory volume in one second, where the mean increase noticed was 280 mL (0.10-0.44), which was an average improvement of 20.58%. In conclusion, the potential role of azithromycin in the treatment of bronchiolitis obliterans is intriguing and it warrants further testing.

Second allogeneic bone marrow transplantation after myeloablative conditioning analysis of 43 cases from single institution.

Between March 1984 and December 1999, a total of 43 second related allogeneic BMT procedures after myeloablative conditioning were carried out in our institution, 37 following allogeneic, and 6 following autologous BMT. Thirty one patients were males (72%). At 1st BMT (BMT1), median age was 11.5 years (range, 0.16-45 years). BMT1 was carried out for the diagnosis of AML in 13 patients (30%), SAA in nine (21%), ALL in six (14%), CML in six (14%), immunodeficiency in three (7%), NHL in two, beta-thal in two, HD in one, Red cell aplasia in one. HLA matching status for allogeneic BMT1 was full match in 33, one antigen mismatch in two and haplo identical in two patients. Median age at the 2nd BMT (BMT2) was 14 years (range, 0.41-46.7 years). Indications for BMT2 were recurrent hematologic neoplasm in 23 patients (53%), primary graft failure in 12 (28%) and late graft failure in 8 (19%). Median time from BMT1 to recurrence of hematologic neoplasm or late graft failure was 10 months (range, 2.5- 88 months). Median BMT1 to BMT2 interval was 13 months (range, 1-107 months). For BMT2, the same donor was used in 29 patients, while 14 patients had alternate related donor (12 full match, 1-one Ag mismatch, 1 haplo identical). A different conditioning regimen was used in the majority of the patients (39, 91%). Radiation containing conditioning regimen were used mostly for patients previously conditioned with chemotherapy only for BMT1 and chemotherapy conditioning +/- ATG for those who received radiation containing conditioning at BMT1. Bone marrow was the stem cell source for all patients at BMT2 and all except three autologous peripheral stem cell transplantation patient at BMT1. Significant organ toxicity leading to procedure related death in 13 patients (30%) was observed after BMT2. At a median follow up of 36 months after BMT2, 22 patients (51%) are alive (20 free of disease, 2 with recurrent disease) with overall median survival of 47.5 (SD +/- 9) months. Univariate analysis of relevant clinical factors identified the following variables as the only statistically significant favorable prognostic factors for overall survival: BMT1-BMT2 interval of > or = 6 months (P=0.0007) and age at BMT2 < or = 10 years (P=0.041). The nature of underlying disease (neoplastic or non-neoplastic) was not statistically significant (P=0.23). There was no statistically significant difference in survival outcome of BMT2 using same donor vs. alternate related donor (P=0.51). Due to the relatively limited sample size, multivariate analysis was not attempted. This single institution study suggests that second allogeneic BMT after myeloblative conditioning has an acceptable treatment related morbidity/mortality and favorable outcome if performed at age < or = 10 years and with an interval of > or = 6 months after the first BMT. Additionally same donor can successfully be used for the second transplant with similar survival outcome to alternate donor.

Hepatitis B virus reactivation with clinical flare in allogeneic stem cell transplants with chronic graft-versus-host disease.

We conducted a retrospective study with the aim of identifying risk factors and clinical characteristics associated with HBV reactivation and clinical flare after allogeneic stem cell transplantation (aSCT). We reviewed the King Faisal Specialist Hospital and Research Center International Bone Marrow Transplant Registry database from January 1998 to June 2000. Complete serological screening for HBV was available in 128 of 131 patients transplanted during that period. Fifty-four (42%) had evidence of prior infection and recovery from HBV before transplant (hepatitis B core antibody positive, B surface antigen negative). Forty-two were evaluable for HBV reactivation and clinical flare. Six (14%) reactivated with clinical flare as documented by seroconversion and/or positive HBV DNA in the serum with biochemical hepatitis at 5.5, 18, 18, 19, 21 and 23 months post-transplant. Five of fifteen patients with chronic graft-versus-host disease (cGVHD) reactivated with clinical flare in contrast to 1/27 without cGVHD (RR: 9.0, 95% CI: 1.2-70.1 P < 0.02). HBV reactivation with clinical flare occurred during immunosuppressive therapy tapering or withdrawal in all patients. In conclusion, hepatitis B core antibody positive allogeneic stem cell recipients with cGVHD are at significant risk of HBV reactivation with clinical flare.

The spectrum of Fusarium infection in immunocompromised patients with haematological malignancies and in non-immunocompromised patients: a single institution experience over 10 years.

Fusarium is a newly emerging fungal pathogen associated with significant morbidity and mortality in the immunocompromised host. We have reviewed our hospital's experience with Fusarium between 1985 and 1995. Fusarium species were isolated from 22 specimens, representing 11 patients. Cases were not clustered by time period. The median age of the patients was 36.5 years (range 17-69 years). The sources of the organism were 12 skin lesions from eight patients, seven blood cultures from two patients and one specimen each from a Hickman catheter tip, nail clippings and a bronchoalveolar lavage. Seven of the patients had chemotherapy-induced neutropenia when the Fusarium was isolated. Five of them developed invasive fusarosis during acute leukaemia induction treatment. They remained neutropenic, and none survived. The other two patients recovered from neutropenia and were treated successfully for this infection. The remaining four patients were not neutropenic or immunocompromised. Three grew Fusarium from skin or nail clippings and one from bronchial alveolar lavage (BAL). There was no evidence of invasive disease in any of the four. None of them received antifungal therapy, and they were all alive at last follow-up. We conclude that Fusarium is a newly emerging infection in neutropenic patients. A high index of suspicion, especially for skin lesions, will help in early diagnosis before systemic and visceral dissemination. Excision of the initial focus of infection and antifungal therapy, aided by speedy neutrophil recovery, are likely to protect patients threatened with these fatal infections. Fusarium isolated from non-neutropenic, non-immunosuppressed patients is not significant and does not merit systemic antifungal treatment.

Mycobacterium tuberculosis infection in allogeneic bone marrow transplantation patients.

Bone marrow transplant (BMT) recipients are prone to bacterial, viral and fungal infections. Mycobacterium tuberculosis infection can occur in these patients, but the incidence is lower than that of other infections. This report describes four patients with Mycobacterium tuberculosis infection identified from 641 adult patients who received a BMT over a 12-year period (prevalence 0.6%). The pre-transplant diagnosis was AML in two patients and CML in the other two. Pre-transplant conditioning consisted of BU/CY in three patients and CY/TBI in one. Graft-versus-host disease (GVHD) prophylaxis was MTX/CsA in three patients and T cell depletion of the graft in one patient. Sites of infection were lung (two), spine (one) and central nervous system (one). Onset of infection ranged from 120 days to 20 months post BMT. Two patients had co-existing CMV infection. One patient had graft failure. The two patients who received anti-tuberculous (TB) therapy recovered from the infection. Although the incidence of tuberculosis in BMT patients is not as high as in patients with solid organ transplants, late diagnosis due to the slow growth of the bacterium can lead to delay in instituting anti-TB therapy. A high index of suspicion should be maintained, particularly in endemic areas.

Case report: isoimmune inhibition of erythropoiesis following ABO-incompatible bone marrow transplantation.

A 26-year-old ABO-O positive patient with aplastic anemia received a bone marrow transplant from his genotypically HLA identical, but ABO-A positive, brother. Engraftment of myeloid and megakaryocytic lineages occurred within 4 weeks but pure red cell aplasia and transfusion dependent anemia persisted for 160 days. The authors postulated that the failure of erythropoiesis was due to a high titer of anti-A isohemagglutinins. They tested this hypothesis with clonal cell cultures and flow cytometric analysis of ABO antigen expression by colony forming cells in vitro. During the period of prolonged red cell aplasia, the patient had normal numbers (85 +/- 12 per 10(6) cells) of circulating donor derived, burst forming units-erythroid (BFU-E). Immunophenotypic analysis of erythroid burst colonies derived from culture of the patient's bone marrow cells showed that 91 +/- 5% of 274 nucleated red cells were A-antigen positive, confirming full donor engraftment. Autologous plasma and complement added on day 1 of culture did not affect the colony growth (82.5 +/- 15 per 10(6) cells). However, when the addition of complement was delayed until day 7 of culture, there was 90% inhibition of BFU-E (7.5 +/- 5 per 10(6) cells) compared to controls (p less than 0.0004). Based on this, the authors propose a model for expression of ABO antigens during erythropoiesis, in which BFU-E do not express ABO antigens but their progeny do. The data support the hypothesis that the mechanism of prolonged pure red cell aplasia after ABO-incompatible bone marrow transplantation is complement mediated immune destruction of erythroid progenitors past the stage of BFU-E in differentiation.

Accumulation of tetrahydrofolates in human plasma after leucovorin administration.

Reduced folates in plasma after i.v. and oral leucovorin administration were estimated by a ternary complex assay based on the incorporation of CH2FH4 into a stable complex with Lactobacillus casei thymidylate synthase and [3H]FdUMP. Each of the reduced folates, CH2FH4, FH4, and 5CH3FH4, could be quantitatively recovered from plasma by this approach even in the presence of high concentrations of the parent compound leucovorin. Examination of the accumulation kinetics of these reduced folates showed that after i.v. administration of 20 mg D,L-leucovorin to a healthy volunteer, FH4 and, to a lesser extent, CH2FH4 accumulated to maximal levels very early (less than 15 min), with a subsequent depletion that had a half-life of approximately 30 min. Accumulation of FH4 reached a peak level that was 12% of the maximal level of 5CH3FH4 achieved and more than 3 times greater than the pretreatment level of this common, circulating reduced folate form. Similar accumulation patterns were observed in a female patient with metastatic colonic cancer who was undergoing methotrexate (MTX)/fluorouracil therapy followed by i.v. leucovorin (15 mg). FH4 also accumulated, but to a lesser extent and over a longer period of time, when the same dose of leucovorin given orally. When several similar doses of leucovorin were given prior to the experimental dose, greater accumulation and duration of the FH4 response was observed. We propose that accumulation of FH4 and CH2FH4 could provide a circulating source of the reduced folate thought to be the active form for both high-dose MTX with leucovorin rescue and enhancement of fluorouracil activity.

Role for aldehyde dehydrogenase in survival of progenitors for murine blast cell colonies after treatment with 4-hydroperoxycyclophosphamide in vitro.

We have studied the effects of 4-hydroperoxycyclophosphamide (4-HC) on murine hemopoietic progenitors. We found dose-dependent killing and differential sensitivities of colony forming cells with burst forming units-erythrocyte being most sensitive and colony-forming units-granulocyte/erythrocyte/macrophage/megakaryocyte most resistant. We also tested the effects of 4-HC on more primitive murine progenitors which were identifiable in our assay system when the addition of interleukin-3 was delayed until Day 7. We found that the sensitivities of the progenitors for blast cell colonies are similar to those of colony-forming units-granulocyte/erythrocyte/macrophage/megakaryocyte and that late-appearing blast cell colonies were particularly resistant to 4-HC. In order to study the mechanism of differential sensitivities of murine progenitors to 4-HC, we examined the sensitivities of murine progenitors to 4-HC after brief incubation with diethylaminobenzaldehyde, an inhibitor of aldehyde dehydrogenase. Progenitors for granulocyte/macrophage colonies, granulocyte/erythrocyte/macrophage/megakaryocyte colonies, and blast cell colonies became more sensitive to 4-HC and the differential sensitivities of the progenitors disappeared following this treatment. We also tested the sensitivities of the progenitors to phenylketophosphamide, an analogue of 4-HC which is resistant to inactivation by aldehyde dehydrogenase. Various colony-forming units exhibited a similar dose response to this compound. These data indicate that intracellular levels of aldehyde dehydrogenase might play an important role in differential sensitivities of murine colony-forming units to 4-HC.

The occurrence of a peripheral T-cell lymphoma in a chronically immunosuppressed renal transplant patient.

A 32-year-old man received a cadavaric renal transplant in 1975 for end-stage renal disease and, thereafter, was treated with azathioprine and methylprednisolone for chronic immunosuppression. In 1985, he presented with fever and pancytopenia that persisted despite withdrawal of the immunosuppressive agents. Lymph node and liver biopsies demonstrated malignant lymphoma within the sinuses of the node and the sinusoids of the liver. A splenectomy was performed for persistent pancytopenia, and the spleen demonstrated malignant lymphoma of the diffuse mixed large and small cell type exclusively within the cords of the red pulp. The immunophenotype of the tumor cells was obtained by frozen section immunoperoxidase staining with monoclonal antibodies and flow cytometric analysis. The tumor cells were positive for the Pan T cell markers CD3 and CD2, but were negative for the subset markers CD4 and CD8. A DNA hybridization study conducted on the splenic tissue conclusively identified the clonal nature of the malignant T cells by demonstrating rearrangement of the T cell receptor beta gene. In spite of multiple chemotherapeutic regimens, the patient developed increasing peripheral blood involvement and died with disseminated lymphoma. This case appears to be unique in that it is the first report of a chronically immunosuppressed transplant recipient to develop a malignant lymphoma of the mature T cell type, and several of the pathologic features of the tumor have not been observed previously.

Hemoglobin SC disease and alpha-thalassemia. Prolonged survival and mild clinical course.

An 86-year-old black woman admitted for an elective cataract extraction was found to have moderate hypochromic microcytic anemia. Hematologic evaluation disclosed the presence of hemoglobin SC disease and heterozygous alpha-thalassemia-2 (alpha alpha/alpha-). A red cell density profile of the patient's peripheral blood revealed an absence of the typical uniform shift toward higher-density values seen in hemoglobin SC disease, indicating a "normalization" in the distribution of intracellular hemoglobin types. It is suggested that the co-inheritance of hemoglobin SC disease and heterozygous alpha-thalassemia-2, probably by decreasing the tendency toward intracellular hemoglobin S polymerization, contributed to her prolonged survival and relatively mild clinical course.