Abstract
The monoclonal anti CD20 antibody Rituximab (RTX) is increasingly used in allogeneic stem cell transplantation (SCT) to treat lymphoproliferative disorders and chronic graft-versus-host disease (GVHD). RTX administration can be complicated by delayed and prolonged neutropenia, but the mechanism is unclear. We report the occurrence of profound cytopenias following RTX given in the conditioning regimen or early after T cell deplete-SCT to treat B cell lymphoproliferative disorders or c-GVHD. Between 2006–2009, 102 patients (median age 43, range 13–68 years), received a myeloablative matched-sibling T cell-deplete SCT for lymphoid or myeloid hematological disorders. Neutropenia occurring within 4 weeks of treatment developed in 16 of 17 patients given RTX within the first 190 days after SCT. Fourteen patients developed severe neutropenia (count < 0.5K/μL) lasting up to 10 months and 12 required hospitalization to treat severe neutropenic infections. Six of the 14 patients died of infection complicating GVHD treatment. Recovery of lymphocytes and immunoglobulins was also delayed, with a significantly lower ALC at 9 months and 12 months post SCT compared to patients with c-GvHD not treated with early RTX (p < 0.02). In contrast, patients receiving RTX one year after SCT experienced only moderate neutropenia 3–5 months after treatment lasting 10–20 days while maintaining ANC > 1.0 × 109/L. Although RTX rapidly controlled c-GVHD, we conclude that its administration early after T cell deplete-SCT is associated with prolonged profound and life-threatening cytopenias, and should be avoided.
Introduction
Allogeneic hematopoietic stem cell transplantation (SCT) offers the possibility of a curative treatment for malignant and non-malignant hematological diseases. However, SCT is frequently complicated by graft-versus-host disease (GvHD), which remains a major cause of transplant-related morbidity and mortality. The anti-CD20 chimeric monoclonal antibody Rituximab (RTX) given prior to, or during conditioning for T cell-replete SCT has been reported to decrease acute (a-GvHD), and chronic (c-GvHD), and may decrease transplant related mortality (TRM) 1–3. Because of these promising results, RTX has been increasingly used to treat c-GvHD 4.
RTX induces response rates in about two thirds of patients with c-GvHD. Response varies by organ, with an estimated response rate of 60% for c-GvHD of the skin compared to approximately 30% for c-GvHD of the GI tract, liver or lung 5. Apart from acute infusion reactions RTX is well tolerated. However, late adverse effects are being identified with increased frequency. Late onset neutropenia is estimated to occur in up to 35% of patients treated for B cell malignancies in the non-SCT setting 6. Thrombocytopenia (platelets < 75K/μL) and anemia (hemoglobin < 10gm/dL) have also been reported, with an incidence of approximately 12% and 6% respectively 7.
Since 2006 we have used RTX in the early transplant period after myeloablative SCT, either as part of the conditioning regimen for B cell malignancies, or to treat emerging c-GvHD. Although patients with c-GvHD responded well to RTX, all patients who received RTX within six months after SCT had a high risk of developing severe cytopenias. Here we describe the clinical outcome of RTX treated patients and discuss the possible etiology of RTX induced cytopenias in this patient population.
Materials and Methods
Patients and Controls
Between February 2004 and April 2009, 102 consecutive patients underwent a T cell–depleted SCT from an HLA-identical sibling in 3 successive National Heart, Lung and Blood Institute (NHLBI) institutional review board–approved protocols (04-H-0112, 06-H-0248, and 07-H-0136). Patients and donors provided written informed consent before enrolling in the transplantation protocol.
All patients received a conditioning regimen of fludarabine 125mg/m2 over 5 days, fractionated TBI 12 Gy (4.0 Gy if over 55y) in eight fractions over 4 days, followed by cyclophosphamide 120 mg/kg over 2 days. All transplants were depleted of T lymphocytes with the Isolex system (protocol 04-H-0112), or with the Miltenyi CliniMacs system (Miltenyi Biotec Inc., Auburn, CA) (protocols 06-H-0248 and 07-H-0136) as previously described 8,9. In protocols 04-H-0112, 06-H-0248 patients received an infusion of donor lymphocytes between days 60–90 after SCT. In protocol 07-H-0136 patients received 5 × 106 selectively depleted CD3+ cells/kg on day 0, as previously described 10.
Only patients surviving 6 months or longer after SCT were included in the analysis to allow sufficient time for the development of c-GvHD, and to exclude patients that experienced early deaths due to unrelated causes. Of 95 the patients surviving 6 months or longer after SCT, 17 received RTX within six months of SCT. Twenty-eight patients developed c-GvHD but did not receive RTX early after SCT (4 received RTX 1–7 years after SCT), 18 of whom received a SCT prior to the use of RTX for treatment of c-GvHD at our institution and were therefore considered the historical controls for this analysis. Fifty patients did not develop c-GvHD and did not receive RTX at any time after SCT. Chronic GvHD was diagnosed and graded consistent with NIH consensus criteria 11.
GvHD prophylaxis
All patients received low-dose (LD) CSA (target plasma level, 100–200 μg/mL), starting on day - 4 and continuing according to protocol to day + 21 or day 90 after SCT. CSA was reinitiated and continued for approximately 3 months after donor lymphocyte infusions given by protocol or to treat incipient rejection as documented by falling counts and falling donor T cell chimerism. CSA was continued or reinitiated if c- GvHD developed, and patients were treated off protocol for c-GVHD refractory to cyclosporine and prednisone.
Infection Prophylaxis and Treatment
Standard prophylaxis against infection included fluconazole and bactrim given for at least 6 months after transplantation, and twice weekly surveillance for CMV DNA by PCR. Treatment of infections was in accordance with the Guidelines for Management in Allogeneic Hematopoietic Stem Cells Transplant Recipients published by the CDC (http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4910a1.htm). G-CSF was administered in all cases to maintain and absolute neutrophil count (ANC) > 500/μL.
RTX Administration and Response Criteria
RTX given in the first 6 months after SCT was administered by intravenous infusions of RTX (375 mg/m2 per infusion) at 2–4 weekly intervals post-transplant to treat c-GVHD (15 patients), EBV lymphoproliferative disease (1 patient), and autoimmune hemolytic anemia (1 patient). Three patients with B cell malignancies that received RTX for treatment of c-GVHD also received RTX immediately prior to, or as part of the SCT conditioning regimen. In addition, 4 patients received RTX 1–7 years post SCT at the same dose and schedule to treat c-GVHD. Response of c-GvHD to RTX was assessed 1 month after the last infusion. Complete response (CR) was defined as resolution of all manifestations of c-GVHD in involved organs. A partial response (PR) was defined as an improvement in one or more involved organ without any progression or new organ involvement. Resistance was defined as no-response or worsening c-GVHD requiring alternative therapy.
Statistical Analysis
Survival was measured to the last contact date or death. Univariate and multivariate analyses were performed using Cox proportional-hazard regression model, including all factors associated with a p-value less than 0.2 by univariate analysis, and all factors statistically different among the early RTX and other groups (p<0.10). A stepwise backward procedure was then used with a cut-off significance level of 0.05 to remove factors from the model. P-values are two-sided, with a type I error rate fixed at 0.05. Statistical analyses were performed with SPSS 15.0 and Prism 4 software.
Results
Chronic GvHD Response to RTX
Eight of the 15 patients that received RTX for treatment of c-GvHD during the first six months after SCT experienced complete remission of all c-GvHD symptoms shortly after RTX administration, 4 patients developed a partial response but continued to require first line c-GvHD treatment, and 3 patients required further second-line treatment (table 1). All 4 patients receiving RTX 1–7 years after SCT responded, 3 with CR and 1 with PR.
Table 1.
Patients with c-GvHD that received RTX within 30 weeks of SCT
| Disease | Week of c-GvHD Onset | Organs involved with chronic GvHD | c-GvHD severity (NIH consensus criteria) | Treatment of chronic GvHD | Other 2nd line Treatments |
Blood counts and immunoglobulin levels during the first 12 months after SCT
Onset of cytopenias occurred a median of 4 weeks after administration of RTX and led to a significant difference in blood counts between the 3 groups (early RTX, c-GVHD without early RTX, no c-GVHD) during the first year after SCT (figures 1A–C). Patients treated within 6 months after SCT with RTX experienced lower absolute neutrophil counts at 6 months and 9 months (p < 0.01). These patients also experienced lower absolute lymphocyte counts throughout the first post transplant year (p < 0.01 at 6, 9, and 12 months), a lower median platelet count at 6 months after SCT (p < 0.01), and lower immunoglobulin levels for up to 2 years post SCT. The median level of IgM was lowest at 9 months after SCT, and occurred 12 months or later for IgG and IgA (figure 1E). Clinically significant anemia requiring RBC transfusions was infrequently noted. However no difference in erythropoeitic activity was noted between the 3 groups as represented by equivalent absolute reticulocyte counts during the first year after SCT, and anemia requiring RBC transfusions occurred infrequently (figure 1D).
Figure 1.
A–E. Median absolute peripheral counts during the first year after SCT, and median absolute IgG immunoglobulin levels during the first 2 years after SCT.
Legend: – – – No c-GvHD; ––– c-GvHD without early RTX; – • – Early RTX
Timing of RTX administration and severity of lymphopenia correlates with duration of neutropenia
The earlier RTX was given after SCT, the longer was the duration of cytopenias. Patients receiving their first dose of RTX at least 20 weeks after SCT experienced relatively short episodes of cytopenias with a mean duration of moderate neutropenia (ANC < 1000 cells/μL) of 1.3 months, and of severe neutropenia (ANC < 500 cells/μL, G-CSF dependence) of 0.6 months. In contrast, patients receiving RTX between 10 and 20 weeks after SCT experienced prolonged neutropenia (mean duration 3.3 months of moderate neutropenia, and 1.7 months of severe neutropenia). Patients treated with RTX within 10 weeks of SCT experienced the longest cytopenias (mean duration of 13.7 months of moderate neutropenia, and 5 months of severe neutropenia) (figure 2). In total, 16 of the 17 patients developed severe neutropenia, 5 of which experienced only a minimal responsive to prolonged G-CSF administration. All 4 patients receiving RTX 1–7 years after SCT experienced only moderate neutropenia 3–5 months after treatment lasting 10–20 days while maintaining ANC > 1.0 × 109/L.
Figure 2.
Timing of RTX administration and duration of neutropenia. Mean duration of cytopenias experienced by patients when treated with their first dose of RTX within various time periods in relation to SCT. Duration of cytopenias inversely correlated with the time interval between RTX administration and SCT; patients that received RTX within 10 weeks of SCT experiencing the longest duration of neutropenia and lymphopenia.
RTX administration was associated with a profound nadir in absolute lymphocyte counts (ALC) occurring within 4 weeks after the administration of the last dose. Patients developing an ALC nadir less than the median of 140 lymphocytes/μL experienced the longest duration of neutropenia (ANC < 1000/μL, median 7 months vs. 1.5 months, p < 0.01). Death due to infection only occurred in this group.
Outcomes
All patients received anti-Candida prophylaxis with fluconazole initiated at time of SCT, and all patients were switched to voriconazole for anti-Aspergillus prophylaxis at the time of c-GvHD diagnosis with introduction of steroid therapy. Fourteen of the 17 patients treated with RTX within 6 months of SCT developed recurrent bacterial infections, with superficial cellulitis, bacterial pneumonia, and septicemia occurring in the majority of cases (table 3). Additionally, 6 patients developed significant fungal infections and 5 died with invasive fungal pneumonia (2 Apergillus, 3 Zygomyces). Four patient developed evidence of autoimmune disorders; 2 with T cell large granular lymphoproliferative disease (T-LGL), with > 30% CD8+CD57+ cytotoxic T cells by flow cytometry of peripheral blood, 1 patient with NK-LGL ( > 90% NK dominance of lymphocytes in bone marrow specimen), and 1 patient with immune thrombocytopenic purpura diagnosed clinically and by increased megakaryocytes in the bone marrow biopsy. Three patients developed a-GvHD overlap syndrome of the gastrointestinal tract which occurred up to 2 ½ years after SCT and was documented by biopsy.
Table 3.
Outcomes of patients treated with RTX within 30 weeks of SCT
| Diagnosis | Week of 1st dose of RTX | # of doses of RTX within 30 weeks of SCT | Bacterial Infections | Fungal Infections | Autoimmune disorders | Outcome | Days Survival post SCT |
|---|---|---|---|---|---|---|---|
| MCL | −8 | 3 | Cellulitis | None | T-LGL | Alive | 815 |
| MCL | −5 | 7 | Cellulitis, pneumonia, septicemia | Zygomycos is pneumonia | GI overlap syndrome | Died fungal pneumonia | 959 |
| CLL | 0 | 5 | Pneumonia, cellulitis, septicemia | Zygomycos is pneumonia | GI overlap syndrome | Died fungal pneumonia | 503 |
| ALL Ph+ | 10 | 2 | Pneumonia, septicemia | S. prolificans | Died ICH | 214 | |
| AML | 12 | 3 | Cellulitis, septicemia | None | Died of Relapse | 218 | |
| ALL Ph+ | 13 | 2 | Pneumonia, septicemia | Aspergillus pneumonia | GI overlap syndrome | Died fungal pneumonia | 443 |
| AML | 15 | 3 | None | None | Alive | 577 | |
| MDS | 15 | 2 | Cellulitis, septicemia | Aspergillus + Zygomycos is pneumonia | T-LGL | Died fungal pneumonia | 414 |
| AML | 16 | 3 | None | None | Alive | 1039 | |
| AML | 16 | 4 | Cellulitis | None | Alive | 430 | |
| MDS/AML | 19 | 3 | Cellulitis, bowel perforation, septicemia | None | ITP | Alive | 759 |
| AML | 20 | 3 | Cellulitis | None | Died Idiopathic Pneumonitis | 195 | |
| ALL Ph+ | 22 | 2 | Pneumonia | None | Alive | 703 | |
| ALL Ph− | 22 | 2 | Cellulitis | None | Alive | 1362 | |
| APL | 23 | 3 | None | None | Alive | 1564 | |
| APL | 23 | 4 | Pneumonia, septicemia | Apergillus pneumonia | NK-LGL GI overlap syndrome | Died fungal pneumonia | 648 |
| CML | 27 | 2 | Cellulitis | None | Alive | 528 |
RTX, Rituximab; SCT, stem cell transplantation; AML, acute myelogenous leukemia; ALL, acute lymphoblastic leukemia; APL, acute promyelocytic leukemia; CML, chronic myelogenous leukemia; CLL, chronic lymphocytic leukemia; NHL, non-Hodgkins Leukemia; MDS, myelodysplastic syndrome; Ph+, Philadelphia chromosome; NK or T-LGL, NK or T cell-large granulocytic leukemia
Patients with c-GvHD treated with RTX early after SCT had higher TRM (64% vs. 18%, p = 0.03) when compared to all other patients with c-GvHD. To exclude selection bias and the possibility that RTX was used only to treat the most recalcitrant forms of c-GvHD, we compared results with historical c-GVHD controls not treated with RTX at our institution (tables 1, 2 & 4). Again, patients with c-GvHD treated with RTX within 6 months of SCT had significantly higher TRM compared with the c-GvHD historical controls (64% vs. 17%, p = 0.02), suggesting that the early administration of RTX increased the risk of TRM independent of c-GvHD status. In univariate and multivariate analysis only RTX administration was associated with increased TRM (HR=5.54, 95% CI 1.12–27.2, p=0.03, figure 3).
Table 2.
Historical Controls, Patients with c-GvHD that did not received RTX early after SCT
| Disease | Indication for RTX | Week of 1st dose of RTX | Week of chronic GvHD Onset | Organs involved with chronic GvHD | c-GvHD severity (NIH consensus criteria) | Treatment of chronic GvHD prior to RTX | # of doses within 30 weeks of SCT |
|---|---|---|---|---|---|---|---|
| MCL | NHL, GVHD | −8 | 13 | Skin, Joints | mild | Pred, CSA | 3 |
| MCL | NHL, GvHD | −5 | 14 | Skin, Joints, GI | moderate | Pred, CSA, MMF | 7 |
| CLL | CLL, GVHD | 0 | 19 | Skin, Liver, GI | moderate | Pred, CSA, Tacro, MMF | 5 |
| ALL Ph+ | GvHD | 10 | 10 | Skin, Liver, GI | moderate | Pred, CSA | 2 |
| AML | GvHD | 12 | 12 | Skin | mild | Pred, CSA | 3 |
| ALL Ph+ | GvHD | 13 | 12 | Skin, GI | moderate | Pred, CSA, MMF | 2 |
| AML | GvHD | 15 | 13 | Skin, Joints | moderate | Pred, CSA, MMF | 3 |
| MDS | GvHD | 15 | 13 | Skin, Joints | moderate | Pred, CSA | 2 |
| AML | EBV LPD | 16 | * | * | * | * | 3 |
| AML | GvHD | 16 | 14 | Skin, Joints, Lung | moderate | Pred, CSA, MMF | 4 |
| MDS/AML | GvHD | 19 | 16 | Skin, Liver, GI | moderate | Pred, CSA, Tacro, MMF | 3 |
| AML | GvHD | 20 | 19 | Skin, Lung | moderate | Pred, CSA, MMF | 3 |
| ALL Ph+ | GvHD | 22 | 16 | Skin, Joints | moderate | Pred, CSA, MMF | 2 |
| ALL Ph− | GvHD | 22 | 16 | Skin, Joints | moderate | Pred, CSA, MMF | 2 |
| APL | GvHD | 23 | 18 | Skin, Joints, Liver | moderate | Pred, CSA, Tacro, MMF | 3 |
| APL | GvHD | 23 | 14 | Skin, Joints, Liver | moderate | Pred, CSA, Tracro, MMF | 4 |
| CML | AIHA | 27 | * | * | * | * | 2 |
Received RTX for PTLD and AIHA
RTX, Rituximab; SCT, stem cell transplantation; AML, acute myelogenous leukemia; ALL, acute lymphoblastic leukemia; APL, acute promyelocytic leukemia; CML, chronic myelogenous leukemia; CLL, chronic lymphocytic leukemia; NHL, non-Hodgkins Leukemia; MDS, myelodysplastic syndrome; Ph+, Philadelphia chromosome; EBV, Epstein-Barr virus; AIHA, autoimmune hemolytic anemia; PhotoPh, Photopheresis; CSA, cyclosporine; Tacro, tacrolimus; Pred, prednisone.
Table 4.
Univariate Analysis of Risk Factors for TRM in Patients with c-GvHD
| Covariable | c-GvHD not receiving early RTX | Patients with c-GvHD treated with RTX < 6 months of SCT | Univariate Analysis p-value |
|---|---|---|---|
| RTX administration | 0/18 patients | 15/15 patients | 0.02 |
| Age | Median 34 (range, 19–48) | Median 41 (range, 30–58) | 0.09 |
| Reason for SCT | 0.73 | ||
| AML | 12 | 5 | |
| ALL | 1 | 4 | |
| CML | 2 | 0 | |
| NHL | 1 | 3 | |
| MDS | 2 | 2 | |
| Disease Risk | 0.69 | ||
| Low | 7 | 1 | |
| Intermediate | 2 | 1 | |
| High | 9 | 12 | |
| Severity of c-GvHD prior to RTX administration | 0.18 | ||
| Mild | 6 | 3 | |
| Moderate | 12 | 11 | |
| Severe | 0 | 0 | |
| Number of organs involved | 0.80 | ||
| 1 | 10 | 2 | |
| 2 | 4 | 7 | |
| 3+ | 4 | 5 | |
| DLI given | 11 | 3 | 0.10 |
RTX, Rituximab; c-GvHD, chronic GvHD; SCT, stem cell transplantation; AML, acute myelogenous leukemia; ALL, acute lymphoblastic leukemia; CML, chronic myelogenous leukemia; NHL, non-Hodgkins Leukemia; MDS, myelodysplastic syndrome; DLI, donor lymphocyte infusion.
Figure 3.
Administration of RTX to treat c-GvHD within 6 months of SCT was associated with higher TRM.
Discussion
Chronic GvHD is a major cause of SCT-related morbidity and mortality, and steroid dependent or resistant patients have a worse prognosis. RTX is effective in the treatment of steroid refractory c-GvHD and has been used increasingly early after SCT to treat c-GVHD in addition to its use in controlling lymphoproliferative disorders. This report highlights a potential risk of RTX administration within 6 months of T cell-depleted SCT.
Although cytopenias are known to occur following RTX administration, severe RTX-induced cytopenias have not been described in the context of allogeneic SCT6,12. Previous reports describe only limited cytopenias when RTX is administered early after T cell-replete SCT 13,14. A possible explanation for the worse outcomes in our patients receiving RTX is that the risk of cytopenias is related to the T cell depletion of the graft which delivers only a limited quantity of B cells to the recipient. In our patients whose allografts were manipulated to remove T lymphocytes, less than 1 × 103 B cells/kg were infused at the time of transplantation, rendering them profoundly B cell depleted. Additionally, the reduced inoculum of T cells in the lymphopenic milieu at time of SCT may have contributed to the risk of cytopenias by predisposing our patients to clonal expansions of small numbers of residual CD8+ T cells, which further enhanced immune imbalance induced by RTX 15,16.
The mechanism of increased TRM with early RTX administration after T cell-deplete SCT in our patient population appears multifactorial involving impaired B–lymphocyte, neutrophil, and T-cell function. Although the half-life of RTX ranges from 2–3 weeks, detectable levels may persist 3–6 months after administration 17,18. Previous studies have demonstrated that RTX administration within 1 year prior to SCT significantly impaired B cell reconstitution and resulted in a significant B cell deficiency lasting up to 2 years after T cell-replete SCT 19. Similar to our experience, the duration of B cell deficiency was also inversely correlated with the time interval between RTX administration and SCT, indicating a profound B cell depleting effect of RTX when given in close proximity to SCT. Compared to other patients, including those with c-GvHD, we found that early RTX recipients had reduced levels of immunoglobulins and an increased risk of infection. It was notable that early RTX recipients had lower median neutrophil counts in the first 9 months after SCT compared with other patients (including those developing c-GVHD that did not receive early RTX). Clearly the prolonged neutropenia contributed to the infectious complications encountered after early RTX administration despite the aggressive use of G-CSF, which provided only temporary improvement of the neutrophil count. The profound lymphopenia accompanying the neutropenia in our patients was striking, and was associated with more severe cytopenias and worse outcome.
The neutropenia and lymphopenia following RTX administration is not easily explained. The cytopenias we observed appear distinct from the effects of c-GvHD because neutrophil, platelet, and lymphocyte counts were significantly lower than in patients developing c-GvHD who did not receive RTX early after SCT. In mice, short-term B cell depletion reduces expansion, activation, and effector cell differentiation of CD4+ T cells, whereas CD8+ activation is not affected 20. A decreased conversion of CD4+ T cells from the naïve to a central memory phenotype is also observed, suggesting that a significant functional and maturational deficiency exists in the CD4+ compartment in the absence of B cell and antigen-specific CD4+ T cell interactions. Similarly in humans, lower CD4+ and CD4+Foxp3+ regulatory T cells are noted in patients with diseases of defective B cell differentiation, and are associated with an inversion of the CD4+/CD8+ ratio and a higher incidence of autoimmune disorders 21. Consequently, the immune dysregulation occurring after B cell depletion suggests an immune-mediated mechanism in the pathogenesis of RTX-associated cytopenias. A recent report demonstrates that patients who develop RTX-associated late onset neutropenia (LON) have inverted CD4+/CD8+ ratios and more pronounced T-cell expansions. Proliferation of T-large granular lymphocytes with increased expression and secretion of Fas and Fas ligand was also noted, and bone marrow evaluation demonstrated dyshematopoiesis with extensive hypoplasia of the granulocytic series, consistent with findings seen in immune-mediated T-LGL 22. The occurrence of LGL and ITP in four patients treated with RTX supports the possibility that RTX induced clonal expansion of autoreactive CD8+ T cells which suppressed neutrophil production. We are now searching for expanded LGL CD8+ T cell clones in all neutropenic RTX recipients.
In conclusion, RTX is a powerful immune modulatory agent that is effective in the treatment of c-GvHD. However, prolonged and life-threatening cytopenias can occur when RTX is administered within 6 months of T cell-depleted SCT. Although the mechanism remains unclear, the increased incidence of auto and alloimmune diseases after RTX administration suggests immune dysregulation. We recommend avoiding RTX administration within 6 months of T cell-deplete SCT to minimize the risk of life-threatening cytopenias and other immune mediated adverse events.
Footnotes
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