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| Drugs | Hematological cytopenia | Management |
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| Rituximab | It causes late onset neutropenia in 37.5% to 48% [44, 45, 55, 56], leucopenia in 19%-24.6[42, 61], anemia in 3% [32], lymphopenia in 40% [32] and rarely thrombocytopenia [44, 45]. | Late onset neutropenia is diagnosis of exclusion. It is suggested to reduce doses of anti CMV medication and MMF in face of neutropenia. In case of persisting neutropenia further doses of rituximab may be avoided. |
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| ATG | It causes leucopenia in 10%-50% [64–67], hemolytic anemia [68]and thrombocytopenia in 10%-26.5% [64, 65]. | Monitor CD3 subset or absolute lymphocyte count. Consider withholding ATG if the platelet count drops below 50,000 per mm3 or the white blood cell (WBC) count drops below 2,000 per mm3. Also consider halving the ATG dose [64, 69], if the platelet count is between 50,000–75,000 per mm3 or the WBC count is between 2,000–3,000 per mm3.
Consider using reduce dose of MMF during ATG administration. |
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| Alemtuzumab | It causes leucopenia in 33.3-42% [70, 71], combined incidence of leucopenia and neutropenia in 47% [72], transient thrombocytopenia 14% [73] and autoimmune thrombocytopenia in 1-2.5% [74, 75]. | Consider dose modification if absolute neutrophil count (ANC) is < 250/all and/or platelet count ≤25,000/all. For first occurrence of cytopenia, alemtuzumab therapy should be withheld. The therapy should be resumed at 30 mg when ANC ≥ 500/all and platelet count ≥ 50,000/all. For second occurrence, alemtuzumab therapy should be withheld and resumed when ANC ≥ 500/all and platelet count ≥ 50,000/all at a dose of 10mg. Consider using reduce doses of MMF during alemtuzumab administration. |
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| Basiliximab | Myelotoxicity is less as compared to rituximab, ATG and Alemtuzumab. Leucopenia occurs in approximately 10%–15% and thrombocytopenia 5% [76, 77]. | It is the preferred agent in setting of hematological cytopenia. Reduction of MMF or anti-CMV medications may be considered in face of persisting leucopenia. |
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| Daclizumab | Myelotoxicity is less and leukocyte, platelet and lymphocyte counts are significantly higher when compared with [78] | It is the preferred agent in setting of hematological cytopenia. Reduction of MMF or anti-CMV medications may be considered in face of persisting leucopenia. |
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| Mycophenolate mofetil (MMF) | It causes leucopenia in 11.8% to 40% of KTR [79–82]. Other manifestation include anemia, thrombocytopenia and pancytopenia which and is frequent cause of dose reduction [23]. | Consider reducing dose or holding MMF temporarily. Anti CMV medications dose reduction or holding it temporarily is also suggested. Reduce dose of MMF with concurrent use of ATG or alemtuzumab may prevent occurrence of hematological cytopenia. |
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| Calcineurin inhibitors | Tacrolimus hematologic abnormalities occur in 16.92% and include anemia, neutropenia and combined neutropenia and thrombocytopenia [10]. Neutropenia is more (28%) in combination with MMF [19].Other manifestation of tacrolimus and cyclosporine include thrombotic microangiopathy[83–87]
| Consider changing tacrolimus to cyclosporine in setting of persistent neutropenia. Reducing dose of MMF with tacrolimus may be considered due to pharmacodynamic and pharmacokinetic interaction between the two agents. In setting of thrombotic microangiopathy consider to change to MTORi or using belatacept. Eculizumab may be considered in setting of thrombotic microangiopathy. |
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| Azathioprine | AZA causes leucopenia / neutropenia in around 50% of KTR [88].Frequency of leucopenia increases significantly following azathioprine dosage exceeding 1.99 mg/kg body weight/day [89].It can cause macrocytosis and megaloblastic changes in bone marrow which in turn can lead to ineffective erythropoiesis and pancytopenia [90–92] | Consider complete blood counts, including platelet counts, weekly during the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage alterations or other therapy changes are necessary.
TPMT genotyping or phenotyping can help identify patients who are at an increased risk of developing AZA toxicity. Avoid using allopurinol with AZA. Reduce the dose of AZA if leucopenia persists. |
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| Mammalian Target of rapamycin Inhibitors (MTOR inhibitors) | MTOR inhibitors causes post-transplant anemia [93] via impair metabolism and absorption [94, 95].They also causes leucopenia and thrombocytopenia [96]. The incidence of leucopenia and thrombocytopenia with everolimus is 11-19% and 10-17% respectively [97].
Both sirolimus [98–100] and everolimus [101, 102] causes thrombotic microangiopathy. | Consider reducing MMF dose and adjusting MTORi to lowest therapeutic level. |
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| Valganciclovir | Neutropenia in 4.9% to 37.5% [3, 103–105] and leucopenia in 10-28% [3, 103, 106–108]. It also causes anemia and thrombocytopenia. | Consider using 450 mg once a day. Dose reduction or temporarily holding the medication can be considered in case of unresolving leucopenia. |
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| Ganciclovir | The incidence of leucopenia is 7.1% to 23.1% [106, 109]. The incidence of thrombocytopenia and anemia is 23.1% and 38.5% [106]. Myelotoxicity is less as compared to valganciclovir [110]. | Use correct doses according to graft function. Consider reducing dose. MMF dose reduction or holding it temporarily during ganciclovir treatment for CMV disease may be considered. |
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| Valaciclovir | Bone marrow toxicity with valaciclovir is mild as compared to valganciclovir or ganciclovir. It causes anemia in 11-14% and leucopenia in 6-14% which was not significant from placebo [111]. | Less myelotoxic and chances of cytopenia are not more than placebo. |
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| Trimethoprim-Sulphamethaxazole (TMP-SMZ) | It causes blood cytopenia including neutropenia/leucopenia, thrombocytopenia and megaloblastic anemia. Trimethoprim inhibits granulopoiesis and erythropoiesis in vitro in a dose-dependent [112].It causes leucopenia in 39.61%, thrombocytopenia in 18.18% and neutropenia among leukopenic patients in 10.38% [13]. | Consider alternative (atovaquone, dapsone and pentamidine) for Pneumocystis jirovecii prophylaxis. |
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| Dapsone | It causes neutropenia [113, 114], agranulocytosis [115, 116] and methemoglobinemia[117–121].The incidence of dapsone induced methemoglobinemia in KTR is 46% [122]. | Consider alternative (atovaquone, dapsone and pentamidine) for Pneumocystis jirovecii prophylaxis. |
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