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Introducao O transplante de medula ossea (TMO) e um metodo de tratamento para algumas doencas que afetam as celulas sanguineas, como anemias, mielodisplasias e leucemias. O procedimento objetiva reconstruir a medula doente ou deficitaria atraves de celulas saudaveis. O TMO pode ser autogenico, medula do proprio paciente; alogenico, medula de um doador, ou ainda feito a partir de celulas precursoras de medula ossea, obtidas do sangue circulante de um doador ou do sangue de cordao umbilical. O Brasil possui um dos maiores bancos de doadores de medula ossea do mundo, todavia sabe-se que as chances de encontrar uma medula ossea que seja compativel e muito rara. Objetivos O objetivo do artigo e analisar o numero de transplantes de medula ossea (TMO), na populacao geral, realizados no Brasil entre os anos de 2015 a 2020. Metodologia Estudo transversal descritivo que traz o numero de transplantes de medula ossea, autologos e alogenicos, realizados no Brasil, entre os anos de 2015 a 2020, por meio dos dados apontados nos boletins anuais de Registro Brasileiro de Transplantes (RBT). Resultados Entre os anos de 2015 a 2020, foram realizados um total de 17.210 transplantes de medula ossea no Brasil, de forma que 6.657 sao alogenicos e 10.553 autologos. A media anual de transplantes foi de aproximadamente 2.868 com desvio padrao (DP) 637,43. Os alogenicos apresentaram uma media anual de 1.109 e os autologos de 1.758, aproximadamente. No periodo entre 2015-2019 houve um crescimento medio anual de 15,8% e um crescimento total de aproximadamente 44% de procedimentos realizados. Entretanto, no periodo entre 2019-2020 houve uma reducao de 16% dos procedimentos. Discussao Diante dos resultados obtidos, constata-se que houve um aumento significativo no numero de procedimentos realizados a respeito dos transplantes de medula ossea entre 2015 e 2020. Assim, destes, os transplantes do tipo autologos tiveram maior destaque. Assim, o crescimento medio e total entre esses anos tem mais evidencia de aumento, se comparado aos anos de 2019 e 2020, em que o numero de procedimentos diminuiu. Conclusao Portanto, o aumento do numero de transplantes no periodo de 2015 a 2019 decorre do aumento da expectativa de vida e da evolucao em tecnologia e no sistema de saude. Inclusive nosso sistema nacional de transplantes e referencia para o mundo. Ademais, justifica-se a queda no numero de procedimentos entre 2019 e 2020 devido a pandemia da Sars-Cov-2.

This phase 2 study evaluated isatuximab as monotherapy or combined with dexamethasone in relapsed/refractory multiple myeloma (RRMM). Patients had RRMM refractory to an immunomodulatory drug (IMiD) and a proteasome inhibitor (PI) or had received ≥3 prior lines of therapy incorporating an IMiD and PI. Patients received isatuximab either as monotherapy (20 mg/kg on days 1, 8, 15, and 22 [once weekly] of cycle 1 followed by 20 mg/kg on days 1 and 15 of subsequent cycles; Isa group) or in combination with dexamethasone (40 mg/d [20 mg/d in patients aged ≥75 years] once weekly; Isa-dex group). Treated patients (N = 164) had received a median of 4 (range, 2-10) prior treatment lines. Patients received a median of 5 (1-24) and 7 (1-22) treatment cycles; at data cutoff, 13 (11.9%) of 109 and 15 (27.3%) of 55 patients remained on treatment in the Isa and Isa-dex arms, respectively. Overall response rate (primary efficacy end point) was 23.9% in the Isa arm and 43.6% in the Isa-dex arm (odds ratio, 0.405; 95% confidence interval, 0.192-0.859; P = .008). Median progression-free survival and overall survival were 4.9 and 18.9 months for Isa, and 10.2 and 17.3 months for Isa-dex. Infusion reactions (mostly grade 1/2) and hematologic abnormalities were the most common adverse events. There was a similar incidence of grade 3 or higher infections in both groups (22.0% and 21.8%). In conclusion, addition of dexamethasone to isatuximab increased response rates and survival outcomes with no detrimental effect on safety. This trial was registered at www.clinicaltrials.gov as #NCT01084252. Key Points: • In myeloma patients with a median 4 prior therapy lines, adding dexamethasone to isatuximab increased response rates from 23.9% to 43.6%. • Dexamethasone improved isatuximab efficacy with no detrimental effect on safety, supporting the use of this combination regimen. © 2021 American Society of Hematology

We compared postrelapse overall survival (OS) after autologous/allogeneic (auto/allo) versus tandem autologous (auto/auto) hematopoietic cell transplantation (HCT) in patients with multiple myeloma (MM). Postrelapse survival of patients receiving an auto/auto or auto/allo HCT for MM and prospectively reported to the Center for International Blood and Marrow Transplant Research between 2000 and 2010 were analyzed. Relapse occurred in 404 patients (72.4%) in the auto/auto group and in 178 patients (67.4%) in the auto/allo group after a median follow-up of 8.5 years. Relapse occurred before 6 months after a second HCT in 46% of the auto/allo patients, compared with 26% of the auto/auto patients. The 6-year postrelapse survival was better in the auto/allo group compared with the auto/auto group (44% versus 35%; P = .05). Mortality due to MM was 69% (n = 101) in the auto/allo group and 83% (n = 229) deaths in auto/auto group. In multivariate analysis, both cohorts had a similar risk of death in the first year after relapse (hazard ratio [HR], .72; P = .12); however, for time points beyond 12 months after relapse, overall survival was superior in the auto/allo cohort (HR for death in auto/auto =1.55; P = .005). Other factors associated with superior survival were enrollment in a clinical trial for HCT, male sex, and use of novel agents at induction before HCT. Our findings shown superior survival afterrelapse in auto/allo HCT recipients compared with auto/auto HCT recipients. This likely reflects a better response to salvage therapy, such as immunomodulatory drugs, potentiated by a donor-derived immunologic milieu. Further augmentation of the post-allo-HCT immune system with new immunotherapies, such as monoclonal antibodies, checkpoint inhibitors, and others, merit investigation.

The performance of multiple myeloma (MM) therapies in a general patient population and specific eligibility criteria that might limit enrollment into randomized controlled trials (RCTs) have not been evaluated in depth. This study aimed to determine if improvements seen with MM therapies in RCTs are reflected in the general patient population and to identify eligibility criteria that can be modified to increase enrollment.The Connect MM Registry is a prospective observational cohort study of patients with newly diagnosed MM (NDMM) in the United States. Using common RCT exclusion criteria collected from 16 published studies, patients in the registry were categorized according to their eligibility for inclusion in RCTs.On the basis of common criteria, 563 of 1406 of registry patients (40.0%) are ineligible for RCTs. Criteria leading to exclusion included M-protein ≤ 1.0 g/dL (25.2%), creatinine2.5 mg/dL (13.9%), low absolute neutrophil count (10.0%), and low hemoglobin (9.6%). Significantly more RCT-ineligible versus RCT-eligible patients had hypercalcemia (11.0% vs. 5.5%), elevated creatinine levels (38.9% vs. 6.2%), low hemoglobin levels (59.5% vs. 39.5%), or International Staging System stage III disease (40.1% vs. 22.1%; P .001 for all comparisons). RCT-ineligible patients had a lower 3-year survival rate than RCT-eligible patients (63% vs. 70%). The incidence of serious adverse events was similar between groups.Of patients with NDMM enrolled in the Connect MM Registry, 40% are ineligible for RCTs. This study provides insight into potential modifications of standard eligibility criteria that can lead to improved RCT design and accelerated enrollment.

Purpose: To evaluate the safety of concurrent treatment with trastuzumab and high-dose chemotherapy (HDC), using cyclophosphamide, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), with autologous hematopoietic progenitor cells support, in patients with HER2+ advanced breast cancer. Experimental Design: Patients with HER2-overexpressing high-risk primary breast cancer (HRPBC; defined as ≥4 involved nodes or inflammatory disease), or metastatic breast cancer (MBC) were eligible. Treatment consisted of a loading dose of trastuzumab at 4 mg/kg (day −5), HDC (days −5 to −2), autologous hematopoietic progenitor cells infusion on day 0, and weekly maintenance trastuzumab (2 mg/kg) from day +1 (minimum of 9 doses). Cardiac monitoring included serial left ventricular ejection fraction measurements before treatment and on days +20 and +65. Results: Thirty-three patients were prospectively enrolled (13 HRPBC, 20 MBC). Toxicity seemed similar to that expected with this HDC regimen alone. Neutrophils and platelets engrafted promptly. There were no cases of grade 4 or 5 toxicity. One patient experienced symptomatic grade 3 acute cardiac failure on day −4, responsive to treatment. Trastuzumab did not alter the pharmacokinetics of HDC. Eleven of twelve MBC patients with measurable disease (nine of them refractory to previous chemotherapy) experienced an objective response (9 complete and 2 partial responses). At median follow-up of 34 (13–58) months, all HRPBC patients remain alive and free of disease; the MBC group has event-free survival and overall survival rates of 45 and 70%, respectively. Conclusions: Incorporation of trastuzumab into HDC (cyclophosphamide, cisplatin, and BCNU) is feasible, with no apparent increased toxicity or pharmacokinetic interactions.

We have performed a phase I dose escalation of 4-Hydroperoxycyclophosphamide (4HC) purging of autologous peripheral blood progenitor cells (PBPCs) to improve the outcome of autologous transplantation for patients with myeloid leukemia. Peripheral blood stem cells were mobilized after cytosine arabinoside of 2 g/m2 every 12 hours × 8 doses with etoposide of 40 mg/kg total dose infused over 4 days, followed by growth factor support. The preparative regimen included Busulfan of 1 mg/kg orally every 6 hours × 16 doses, followed by etoposide of 60 mg/kg × 1 day (the patient with chronic myeloid leukemia received cyclophosphamide of 60 mg/kg/d × 2 days in lieu of etoposide). PBPCs purged with 4HC were infused following this induction. Toxicities included grade 3 or 4 skin rashes, stomatitis/mucositis, and delay in time to hematopoietic recovery. The maximum tolerated dose of 4HC used to purge PBPCs in this trial was 20 μg/mL, which resulted in an average of 18 days for white blood cells and 28 days for platelet recovery. With a median follow-up of 2.25 years in surviving patients, the 3-year disease free survival rate is 44% and the overall survival rate is 89%. These data suggest that autologous PBPCs are more sensitive than marrow purged with 4HC, tolerating less intense purging, although a survival advantage may still be seen and should be assessed in larger studies. Approaches to minimize stomatitis and protect normal stem cells from the toxicity of 4HC may improve the tolerance and efficacy of this approach. © 2003 American Society for Blood and Marrow Transplantation Biology of Blood and Marrow Transplantation 9:183-188 (2003)

Background:Carfilzomib (CFZ) is a novel irreversible proteasome inhibitor (PI) approved for relapsed/refractory multiple myeloma, but its safety and efficacy in AL amyloidosis is not known. We report updated results of an investigator-initiated, multi-center, Phase I/II study of CFZ in AL (NCT01789242), including additional patients (pts) treated in the expansion cohort. Methods: Eligible pts (relapsed or refractory AL after ≥1 prior therapy; Mayo cardiac stage I or II; LVEF ≥40%; CrCl≥30; CFZ-naive) received CFZ over 30 minutes on days 1, 2, 8, 9, 15, 16 every 28 days, for 8 cycles, given at 20 mg/m2 on days 1, 2 of cycle 1, then at 27, 36, or 45 mg/m2 (depending on cohort) thereafter. Pre-CFZ hydration was recommended during cycle 1, but could be modified or omitted at investigator discretion. Responding pts could continue on a day 1, 2, 15, 16 schedule at investigator discretion. Dexamethasone 20mg with each CFZ dose was added if no VGPR after cycle 4. Primary objectives were safety and determination of MTD. A 3+3 dose escalation design was used, with a planned expansion cohort at MTD. Responses were based on updated AL consensus guidelines. Pts completing ≥2 cycles (or progressing before 2 cycles) were evaluable for response; all treated pts were evaluated for safety. Cardiac function was monitored in all pts by serial NT-proBNP and echocardiograms. Data cutoff was 6/23/16. Results: From June 2013 - June 2016, 28 eligible pts were enrolled and treated. Median age was 64 (range 43 - 81); 64% were male. Median time from diagnosis was 31 mos., with median of 2 prior regimens (range 1-5), including bortezomib (96%), IMiDs (43%) and stem cell transplant (46%). Thirteen (46%) were refractory to last therapy, and 10 (36%) were PI-refractory (9 bortezomib, 1 ixazomib). Involved organs included kidney (64%), heart (50%), nerve (25%), GI tract (21%), soft tissue (14%), and liver (11%); 13 pts had ≥2 major organs involved. Median baseline NT-proBNP was 542 pg/ml (range 20 - 13571), and median baseline difference in free light chains (dFLC) was 138 mg/L (range 44 - 4709). There were no DLTs at 20/27 and 20/36 mg/m2. At 20/45 mg/m2, there were 2 first-cycle DLTs of grade 3 fatigue ≥7 days, making 20/36 mg/m2 the MTD. Eighteen more pts have enrolled at MTD. Median number of cycles is 6 (range 1-25+), with 10 pts completing the planned 8 cycles (7 continuing on maintenance), 3 ongoing before cycle 8, and 15 stopping early (9 for AE’s, 4 for no response, 2 other). Most common drug-related AE’s to date are fatigue (36%), increased creatinine (29%), nausea (25%), dyspnea (18%), anemia (18%), diarrhea (14%), pyrexia, chills, and hypertension (11% each). Grade 3/4 AEs (all-cause) occurred in 20 (71%) pts, including several grade 3/4 cardiac or pulmonary AEs: hypoxia (n=1), lung infection (n=2), chest pain (n=1), hypotension (n=1), hypertension (n=3), decreased ejection fraction/CHF (n=3), and symptomatic ventricular tachycardia (n=2, 1 with cardiac arrest requiring defibrillation). There have been no grade 5 AEs. Of 24 response-evaluable pts, 15 (63%) have responded hematologically (3 CR, 8 VGPR, 4 PR), including 6 of 8 evaluable PI-refractory pts (1 CR, 2 VGPR, 3 PR). Responses have occurred at all dose levels (Table). Dex was added in 5 pts, with 3 response upgrades. Five (21%) pts have had organ responses (3 kidney, 1 GI, 1 liver) to date. With median follow-up of 16 mos. (range 0.5 - 32), 9 pts have had hematologic progression, and 2 have died. To date, 11 pts have had NTproBNP increases of ≥30% and ≥300 pg/ml on CFZ. For 5 this correlated with progressive clinical and/or echocardiographic signs of cardiac dysfunction; the other 6 lacked objective signs of worsening cardiac function, with either no symptoms (n=4) or progressive fatigue (n=2). Conclusions: CFZ monotherapy is feasible and effective in relapsed/refractory AL amyloidosis, with MTD identified as 20/36 mg/m2 as a 30-minute infusion. Hematologic response rates are promising in this bortezomib-exposed population, including in PI-refractory pts. Cardiac, pulmonary, and renal toxicities were common, warranting close monitoring and dose reductions as appropriate. Similar to IMiDs, NT-proBNP can increase in pts receiving CFZ, without always correlating with progressive cardiac dysfunction, potentially confounding its use as a marker of cardiac response/progression in this setting. Download : Download high-res image (125KB) Download : Download full-size image Disclosures Cohen: Bristol-Meyers Squibb: Consultancy, Research Funding; Janssen: Consultancy. Landau: Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx/Amgen: Research Funding; Janssen: Consultancy. Scott: Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees. Kaufman: Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy; Incyte: Consultancy. Vesole: Janssen: Speakers Bureau; Novartis: Speakers Bureau; Celgene: Speakers Bureau; Takeda: Speakers Bureau; Amgen: Speakers Bureau. Lentzsch: BMS: Consultancy; Celgene: Consultancy, Honoraria. Gomes: Criterium, Inc: Employment. Comenzo: Karyopharm: Research Funding; Janssen: Consultancy, Research Funding; Prothena: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Durie: Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy.

Although multiple myeloma remains incurable outside of allogeneic hematopoietic stem cell transplantation, novel agents made available only in the last few decades have nonetheless tremendously improved the landscape of myeloma treatment. Lenalidomide, of the immunomodulatory class of drugs, is one of those novel agents. In the non-transplant and relapsed/refractory settings, lenalidomide clearly benefits patients in terms of virtually all meaningful outcomes including overall survival. Data supporting the usage of lenalidomide as part of treatment approaches incorporating high-dose chemotherapy with autologous stem cell support (ASCT) are less mature as pertains to such long-term outcomes and toxicity, and lenalidomide is not currently approved by regulatory agencies for use in the context of ASCT in either the United States or Europe. That said, relatively preliminary efficacy data describing lenalidomide as a component of ASCT-based treatment approaches to MM are indeed promising, and consequently lenalidomide’s role in ASCT-based treatment strategies is growing. In this review we summarize existing data that pertains to lenalidomide in the specific context of ASCT, and we share our thoughts on how our own group applies these data to approach this complex issue clinically.

We present a study of the prevalence of genetic polymorphisms and expression of genes encoding the drug-resistance proteins glutathione S-transferases (GSTs) in order to gain insights into the pattern of failure evident in mantle cell lymphoma. We note a high preponderance of genetic alterations conferring resistance to standard chemotherapy in this illness. Concurrent with this investigation, we present a series of patients who were provided dose-dense and intense chemotherapy to circumvent these drug-resistance mechanisms. High responses were noted, though durable remissions were few, indicating non-traditional chemotherapy options are important to investigate in this illness.

This study reports the development of an assay, the Pre-colony-forming unit (CFU) assay, which detects human hematopoietic precursors. The Pre- CFU assay is based on the observation that precursors to CFU- granulocyte-macrophage (CFU-GM) that are undetectable in clonogenic assays differentiate into CFU-GM preferentially following treatment in suspension culture with recombinant human interleukin-1 alpha (rhIL-1 alpha) combined with rhIL-3. Using the Pre-CFU assay, hematopoietic precursors were detected in human bone marrow depleted of CFU-GM progenitors and differentiated hematopoietic elements via 4- hydroperoxycyclophosphamide treatment coupled with selection for CD34+ cells (4-HCresistant/CD34+ marrow). Additionally, the Pre-CFU assay detected recovery of hematopoiesis substantially earlier than the CFU- GM assay in primates following myeloablation with 5-fluorouracil. The Pre-CFU assay was used to asses purification of a phenotypically defined hematopoietic precursor population, the lin-CD34+ population. The lin-CD34+ population lacks detectable surface markers for T-cell, B- cell, natural killer cell, and myeloid lineage, possesses the CD34 antigen, is devoid of CFU-GM progenitors, and yields Pre-CFU assay values comparable with 4-HCresistant/CD34+ marrow. Using a combination of phenotypic analysis and Pre-CFU assay analysis, the action of rhIL-1 alpha plus rhIL-3 treatment on lin-CD34+ cells was further characterized. The data indicate that rhIL-1 alpha plus rhIL-3 treatment induces proliferation and differentiation of early hematopoietic precursors into progenitors and terminally differentiated cells, without inducing a significant expansion of the precursor population itself.

PROGRESSION

Neurological paraneoplastic syndromes are a rare group of disorders that occur in 1-2% of people with malignancy. They are usually caused by an immune response, triggered by and directed against a tumour, that cross-reacts with protein expressed by the peripheral or central nervous system. Any part of the nervous system can be affected and patients often develop severe and permanent disability. Diagnosis can be difficult as in two-thirds of patients the neurological problems appear up to 5 years before the tumour manifests. However, certain of these syndromes are often associated with specific serum autoantibodies that can be useful both in diagnosis of the neurological syndrome and in focusing the search for a particular tumour. Thus, these antibodies can allow earlier identification and treatment of cancer and, potentially, a reduction in morbidity and mortality. It was only in the 1980s that the first anti-neuronal autoantibodies were characterized and their associations with clinical syndromes and tumours defined. Further antibodies have been isolated over the past 20 years and novel pathogenic mechanisms for several syndromes have been recognized. For example, voltage-gate ion channels seem to be a common target for autoantibodies involved in peripheral nerve diseases such as the Lambert-Eaton myasthenic syndrome and neuromyotonia (Isaacs' syndrome). However, the place of most paraneoplastic antibodies in the pathogenesis of central syndromes is yet to be fully elucidated.

Reduction in the toxicity of allogeneic transplantation with nonmyeloablative induction regimens has expanded the scope of practice to older and more debilitated patients. However, the limited availability of matched sibling donors requires that alternative donor sources be investigated. Reported here are 2 cases of patients with advanced hematologic malignancies without matched siblings, partially matched family members, or matched unrelated donors who successfully underwent nonmyeloablative conditioning therapy followed by infusion of partially matched, unrelated-donor cord blood cells. The patients are in remission and remain 100% donor as assessed by short tandem repeat analysis of the marrow 6 and 12 months following transplantation.

A246 VMP Results in Fewer Bone Events and Greater ALP Increases Versus MP in the VISTA Study in Front-Line MM M Delforge,1 M Kropff,1 I Spicka,2 M Petrucci,3 PG Richardson,4 R Schlag,5 N Khuageva,6 MA Dimopoulos,7 O Shpilberg,8 O Samoilova,9 MV Mateos,10 K Liu,11 W Deraedt,12 H van de Velde,13 J San Miguel14 1University of Munster, Germany; 2University Hospital, Prague, Czech Republic; 3University La Sapienza, Rome, Italy; 4Dana-Farber Cancer Institute, Boston, MA; 5Praxisklinik Dr. Schlag, Wurzburg, Germany; 6SP Botkin Moscow City Clinical Hospital, Russian Federation; 7University of Athens, School of Medicine, Athens, Greece; 8Rabin Medical Center, Petah-Tiqva, Israel; 9Nizhnii Novgorod Region Clinical Hospital, Russian Federation; 10Hospital Universitario Salamanca, CIC, IBMCC (USAL-CSIC), Spain; 11Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan; 12Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium; 13Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium; 14Hospital Universitario Salamanca. CIC, IBMCC (USAL-CSIC), Salamanca, Spain

In a pre-clinical primate model, the effect of a single intravenous injection of rh-GM-CSF (50 micrograms/kg), rh-IL3 (20 micrograms/kg), rh-IL-1 beta (1 micrograms/kg), rh-G-CSF (50 micrograms/kg) and rh-pIXY 321 (50 micrograms/kg) on peripheral blood mononuclear cell and hematopoietic stem cell concentration was determined. The results indicated that administration of a single dose of rh-IL-1 beta increased the concentrations of hematopoietic stem cells, including CFU-GM progenitors and precursors to CFU-GM. No toxicity was noted with this procedure. None of the remaining cytokines tested caused a significant increase in the peripheral blood hematopoietic stem cell concentration when administered in this manner and only G-CSF caused an increase in peripheral blood mononuclear cell concentrations. Autologous transplantation with limiting numbers of peripheral blood mononuclear cells (1 x 10(7) cells/kg) collected either 24 or 72 h following injection of 1 microgram/kg rh-IL-1 beta conferred a survival advantage to recipients compared with controls. These results imply that a single intravenous administration of rh-IL-1 beta may increase the concentration of peripheral blood stem cells to levels sufficient for transplantation.

8024^ Background: AL amyloidosis is a monoclonal plasma cell disorder with progressive organ dysfunction and short survival. Standard non-transplant AL therapy is melphalan (M) + dexamethasone (D). As adding bortezomib (Bz) to M+ Prednisone improved outcomes in myeloma, we sought to determine if adding Bz to MD improves outcomes in AL. Methods: Eligibility: ECOG PS ≤ 3, Cr ≤ 5 mg/dL, T.Bili ≤ 2.5 × IULN, ALT/AST ≤ 3 × IULN, ANC ≥ 1.0 K/mm3, PLT ≥ 80 K/mm3, peripheral neuropathy (PN) ≤ Gr 2 (≤ 1 if painful), no lower limit for LVEF. Design: Two-stage phase II study. Stage I: 16 pts with biopsy-proven AL, light chain deposition disease (LCDD) or smoldering myeloma with amyloid (SMM). 1o endpoint: complete hematologic responses (cHR). If ≥5 cHRs observed, then 2nd stage with 17 more pts, giving 90% power to detect a true cHR rate of 50%. 2o endpoints: overall HR, organ response (OrR), and survival. Therapy: M (9 mg/m2 PO d 1-4; 6 mg/m2 if Cr > 2.5 mg/dL), Bz (1.3 mg/m2 IV d 1, 8, 15, 22; 1.0 mg/m2 if baselin...

We studied escalating doses of recombinant human interleukin-1 beta (IL-1 beta) alone and after a myelosuppressive dose of 5-fluorouracil (5-FU) in patients with gastrointestinal cancer. Transient neutropenia, monocytopenia, and lymphocytopenia were observed followed by a 1.3- to 6.0-fold (mean, 3.46-fold) dose-dependent neutrophil leukocytosis (P less than .00001) on the days of IL-1 beta administration. Increases in platelet counts were observed at a median of 14 days (range, 6 to 23) after IL-1 beta administration. Transient hypoglycemia, rebound hyperglycemia, elevations in serum cortisol, and C-reactive protein were observed. Side effects included fever, rigors, and headache in the majority of patients. Hypotension was observed in three of five patients at the highest dose level (0.1 micrograms/kg) and was dose-limiting. Fewer days of neutropenia were noted after 5-FU plus IL-1 beta than after 5-FU alone; however, this difference did not reach statistical significance. These data show that IL-1 beta has stimulatory effects in human hematopoiesis.

The effects of recombinant human interleukin-1 rhIL-1 beta (rhIL-1b) on hematopoietic recovery following chemotherapy in a primate model were investigated. Cynomolgus monkeys received 1 microgram/kg/day rhIL-1b intravenously for 2, 7, and 14 days following 5-Fluorouracil (5-FU) treatment (75 mg/kg x 2 days). Compared with controls, a significantly shortened time to achieve an absolute neutrophil (ANC) count over 500/microL was observed in animals receiving 2- and 7-day courses of rhIL-1b (17 v 30 days), while animals receiving a 14-day course of rhIL-1b achieved an ANC over 500/microL by 23 days. Concomitantly, a marked increase in granulocyte-macrophage colonies (CFU-GM) was observed at 14 days following 5-FU in animals receiving 2- and 7-day rhIL-1b courses. In animals receiving a 14-day rhIL-1b course, a significant increase in CFU-GM relative to control was not seen until 21 days post 5-FU. Utilizing a serum-free colony assay system, a 50% inhibition of normal marrow CFU-GM growth was observed with the addition of sera obtained on day 9 post 5-FU from animals receiving rhIL-1b for 14 days. Sera obtained at any time from animals receiving 2- and 7-day rhIL-1b treatment did not show any growth inhibition. Addition of antibodies to TNFa to the coculture assay abrogated the CFU-GM growth inhibition. TNFa levels in sera with the inhibitory activity was relatively high (918 pg/mL). Our data indicate that rhIL-1b enhances hematopoietic recovery following 5-FU if administered for short periods of time (less than 7 days), whereas prolonged administration has a counterproductive effect that is due in part to the induction of TNFa production.